Side-chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers

ABSTRACT

Methods of treating or suppressing mitochondrial diseases, such as Friedreich&#39;s ataxia (FRDA), Leber&#39;s Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS), or Kearns-Sayre Syndrome (KSS) are disclosed, as well as compounds useful in the methods of the invention. Methods and compounds useful in treating other disorders are also disclosed. Energy biomarkers useful in assessing the metabolic state of a subject and the efficacy of treatment are also disclosed. Methods of modulating, normalizing, or enhancing energy biomarkers, as well as compounds useful for such methods, are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of U.S. Provisional ApplicationNo. 60/776,028, filed Feb. 22, 2006, and of U.S. Provisional ApplicationNo. 60/873,395, filed Dec. 6, 2006. The entire contents of thoseapplications are hereby incorporated by reference herein.

TECHNICAL FIELD

The application discloses compositions and methods useful for treatmentor suppression of diseases due to mitochondrial disorders, such asFriedreich's ataxia, Leber's Hereditary Optic Neuropathy, Kearns-SayreSyndrome, and mitochondrial myopathy, encephalopathy, lactacidosis,stroke, and for modulating energy biomarkers in a subject.

BACKGROUND

Mitochondria are organelles in eukaryotic cells, popularly referred toas the “powerhouse” of the cell. The molecule adenosine triphosphate(ATP) functions as an energy “currency” or energy carrier in the cell,and eukaryotic cells derive the majority of their ATP from biochemicalprocesses carried out by mitochondria. These biochemical processesinclude the citric acid cycle (the tricarboxylic acid cycle, or Kreb'scycle), which generates reduced nicotinamide adenine dinucleotide(NADH+H⁺) from oxidized nicotinamide adenine dinucleotide (NAD⁺), andoxidative phosphorylation, during which NADH+H⁺ is oxidized back toNAD⁺. (The citric acid cycle also reduces flavin adenine dinucleotide,or FAD, to FADH₂; FADH₂ also participates in oxidative phosphorylation.)

The electrons released by oxidation of NADH+H⁺ are shuttled down aseries of protein complexes (Complex I, Complex II, Complex III, andComplex IV) known as the respiratory chain. These complexes are embeddedin the inner membrane of the mitochondrion. Complex IV, at the end ofthe chain, transfers the electrons to oxygen, which is reduced to water.The energy released as these electrons traverse the complexes is used togenerate a proton gradient across the inner membrane of themitochondrion, which creates an electrochemical potential across theinner membrane. Another protein complex, Complex V (which is notdirectly associated with Complexes I, II, III and IV) uses the energystored by the electrochemical gradient to convert ADP into ATP.

The citric acid cycle and oxidative phosphorylation are preceded byglycolysis, in which a molecule of glucose is broken down into twomolecules of pyruvate, with net generation of two molecules of ATP permolecule of glucose. The pyruvate molecules then enter the mitochondria,where they are completely oxidized to CO₂ and H₂O via oxidativephosphorylation (the overall process is known as aerobic respiration).The complete oxidation of the two pyruvate molecules to carbon dioxideand water yields about at least 28-29 molecules of ATP, in addition tothe 2 molecules of ATP generated by transforming glucose into twopyruvate molecules. If oxygen is not available, the pyruvate moleculedoes not enter the mitochondria, but rather is converted to lactate, inthe process of anaerobic respiration.

The overall net yield per molecule of glucose is thus approximately atleast 30-31 ATP molecules. ATP is used to power, directly or indirectly,almost every other biochemical reaction in the cell. Thus, the extra(approximately) at least 28 or 29 molecules of ATP contributed byoxidative phosphorylation during aerobic respiration are critical to theproper functioning of the cell. Lack of oxygen prevents aerobicrespiration and will result in eventual death of almost all aerobicorganisms; a few organisms, such as yeast, are able to survive usingeither aerobic or anaerobic respiration.

When cells in an organism are temporarily deprived of oxygen, anaerobicrespiration is utilized until oxygen again becomes available or the celldies. The pyruvate generated during glycolysis is converted to lactateduring anaerobic respiration. The buildup of lactic acid is believed tobe responsible for muscle fatigue during intense periods of activity,when oxygen cannot be supplied to the muscle cells. When oxygen againbecomes available, the lactate is converted back into pyruvate for usein oxidative phosphorylation.

Genetic defects in the proteins making up the respiratory chain lead tosevere disease states. One such disease is Friedreich's ataxia (FRDA orFA). Friedreich's ataxia is an autosomal recessive neurodegenerative andcardiodegenerative disorder caused by decreased levels of the proteinfrataxin. Frataxin is important for the assembly of iron-sulfur clustersin mitochondrial respiratory-chain complexes. Estimates of theprevalence of FRDA in the United States range from 1 in every22,000-29,000 people (see World-Wide-Web address.nlm.nih.gov/medlineplus/ency/article/001411.htm) to 1 in 50,000 people(World-Wide-Web address.umc-cares.org/health_info/ADAM/Articles/001411.asp). The disease causesthe progressive loss of voluntary motor coordination (ataxia) andcardiac complications. Symptoms typically begin in childhood, and thedisease progressively worsens as the patient grows older; patientseventually become wheelchair-bound due to motor disabilities.

Another disease linked to mitochondrial dysfunction is Leber'sHereditary Optic Neuropathy (LHON). The disease is characterized byblindness which occurs on average between 27 and 34 years of age(World-Wide-Web address.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=535000); blindness can developin both eyes simultaneously, or sequentially (one eye will developblindness, followed by the other eye two months later on average). Othersymptoms may also occur, such as cardiac abnormalities and neurologicalcomplications.

Yet another devastating syndrome resulting from mitochondrial defects ismitochondrial myopathy, encephalopathy, lactacidosis, and stroke(MELAS). The disease can manifest itself in infants, children, or youngadults. Strokes, accompanied by vomiting and seizures, are one of themost serious symptoms; it is postulated that the metabolic impairment ofmitochondria in certain areas of the brain is responsible for cell deathand neurological lesions, rather than the impairment of blood flow asoccurs in ischemic stroke. Other severe complications, includingneurological symptoms, are often present, and elevated levels of lacticacid in the blood occur.

Another mitochondrial disease is Kearns-Sayre Syndrome (KSS). KSS ischaracterized by a triad of features including: (1) typical onset inpersons younger than age 20 years; (2) chronic, progressive, externalophthalmoplegia; and (3) pigmentary degeneration of the retina. Inaddition, KSS may include cardiac conduction defects, cerebellar ataxia,and raised cerebrospinal fluid (CSF) protein levels (e.g., >100 mg/dL).Additional features associated with KSS may include myopathy, dystonia,endocrine abnormalities (e.g., diabetes, growth retardation or shortstature, and hypoparathyroidism), bilateral sensorineural deafness,dementia, cataracts, and proximal renal tubular acidosis. Thus, KSS mayaffect many organ systems.

The four diseases above appear to be caused by defects in complex I ofthe respiratory chain. Electron transfer from complex I to the remainderof the respiratory chain is mediated by the compound coenzyme Q (alsoknown as ubiquinone). Oxidized coenzyme Q (CoQ^(ox) or ubiquinone) isreduced by complex I to reduced coenzyme Q (CoQ^(red) or ubiquinol). Thereduced coenzyme Q then transfers its electrons to complex III of therespiratory chain (skipping over complex II), where it is re-oxidized toCoQ^(ox) (ubiquinone). CoQ^(ox) can then participate in furtheriterations of electron transfer.

Very few treatments are available for patients suffering from thesediseases. Recently, the compound idebenone has been proposed fortreatment of Friedreich's ataxia. While the clinical effects ofidebenone have been relatively modest, the complications ofmitochondrial diseases can be so severe that even marginally usefultherapies are preferable to the untreated course of the disease. Anothercompound, MitoQ, has been proposed for treating mitochondrial disorders(see U.S. Patent Application Publication No. 2005/0043553); clinicalresults for MitoQ have not yet been reported. For KSS, administration ofcoenzyme Q10 (CoQ10) and vitamin supplements have shown only transientbeneficial effects in individual cases.

Accordingly, there is a serious and unmet need for effective treatmentsof mitochondrial disorders, such as Friedreich's ataxia, Leber'shereditary optic neuropathy, MELAS, and Keams-Sayre Syndrome.

The ability to adjust biological production of energy has applicationsbeyond the diseases described above. Various other disorders can resultin suboptimal levels of energy biomarkers (sometimes also referred to asindicators of energetic function), such as ATP levels. Treatments forthese disorders are also needed, in order to modulate one or more energybiomarkers to improve the health of the patient. In other applications,it can be desirable to modulate certain energy biomarkers away fromtheir normal values in an individual that is not suffering from disease.For example, if an individual is undergoing an extremely strenuousundertaking, it can be desirable to raise the level of ATP in thatindividual.

DISCLOSURE OF THE INVENTION

The invention embraces methods of treating a mitochondrial disorder,modulating one or more energy biomarkers, normalizing one or more energybiomarkers, or enhancing one or more energy biomarkers, comprisingadministering to a subject a therapeutically effective amount oreffective amount of one or more compounds as described herein. Theinvention also embraces compounds as described herein, which are usefulfor treating a mitochondrial disorder, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers.

In one embodiment, the invention embraces a method of treating amitochondrial disorder, modulating one or more energy biomarkers,normalizing one or more energy biomarkers, or enhancing one or moreenergy biomarkers, comprising administering to a subject atherapeutically effective amount or effective amount of one or morecompounds of the formula:

wherein the bond indicated with a dashed line can be single or double;

where R₁, R₂, and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —O—R₅, —S—R₅, —CN, —F,—Cl, —Br, —I, —N₃, and —NR₅R₆; where R₅ and R₆ are independentlyselected from the group consisting of —H, —C₁-C₅ alkyl, —C₃-C₆cycloalkyl, —C₁-C₅ haloalkyl, aryl, heteroaryl, —(C═O)—C₀-C₈ alkyl, and—(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or where R₅ and R₆ selectedfrom these groups are combined to form a ring;

where R₄ represents a linear or branched group containing 1 to 32 carbonatoms and any number of single, double, or triple bonds in anychemically possible combination;

where X is selected from the group consisting of —H, —F, —Cl, —Br, —I,—CN, —N₃, —NR₇R₈, and —OR₉;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁ and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH2)_(p)—, R₂₁ is —(CH2)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ andR₂₁, together with the nitrogen atom to which they are attached combineto form a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

with the proviso that when both of R₁ and R₂ are —OMe and R₃ is -Me,then X is not —H or —OH;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, R₁, R₂, and R₃ are independently selected fromthe group consisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —S—R₅,—CN, —F, —Cl, —Br, —I, —N₃, and —NR₅R₆. In another embodiment, R₁, R₂,and R₃ are independently selected from —H —C₁-C₅ alkyl, —C₁-C₅haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and—C₂-C₅ haloalkynyl. In another embodiment, at least one of R₁, R₂, andR₃ is independently selected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl. Inanother embodiment, at least one of R₁, R₂, and R₃ is independentlyselected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, with the proviso that Xis not —H. In another embodiment, at least two of R₁, R₂, and R₃ areindependently selected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl. Inanother embodiment, R₁, R₂, and R₃ are independently selected from—C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl,—C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl. In another embodiment, R₁ and R₂ are—CH₃, R₄ is —CH₂CH₂—, and X is —H. In another embodiment, the one ormore compounds are selected from compounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, R₁ and R₂ are —CH₃, R₄ is a bond, and X is —OH.

In another embodiment, the one or more compounds are selected fromcompounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, R₄ is —(CH₂)_(n)C(CH₃)₂—, where n is an integerfrom 0 to 15 inclusive; in another embodiment, X is —H or —OH.

In another embodiment, R₄ is a bond, where n is an integer from 0 to 15inclusive; in another embodiment, X is —H or —OH.

In another embodiment, R₅ is selected from the group consisting of —H,—C₂-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, and heteroaryl.In another embodiment, R₅ is —C₂-C₅ alkyl. In another embodiment, atleast one of R₁, R₂, and R₃ is independently selected from —C₁-C₅ alkyl,—C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl,and —C₂-C₅ haloalkynyl. In another embodiment, at least two of R₁, R₂,and R₃ are independently selected from —C₁-C₅ alkyl, —C₁-C₅ haloalkyl,—C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅haloalkynyl. In another embodiment, R₁, R₂, and R₃ are independentlyselected from —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl. In anotherembodiment, R₅ is selected from the group consisting of —H, —C₂-C₅alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, and heteroaryl, suchas —C₂-C₅ alkyl; one, two, or three of R₁, R₂, and R₃ are independentlyselected from —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl; and R₄ is—(CH₂)_(n)C(CH₃)₂—, where n is an integer from 0 to 15 inclusive. Inanother embodiment, X is —H or —OH.

In another embodiment, the invention embraces a method of treating amitochondrial disorder, modulating one or more energy biomarkers,normalizing one or more energy biomarkers, or enhancing one or moreenergy biomarkers, comprising administering to a subject atherapeutically effective amount or effective amount of one or morecompounds of the formula:

where n is an integer from 0 to 9 inclusive, and each unit can be thesame or different;

wherein the bonds indicated with dashed lines can be single or double;

where R₁, R₂, and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —O—R₅, —S—R₅, —CN, —F,—Cl, —Br, —I, —N₃, and —NR₅R₆; where R₅ and R₆ are independentlyselected from the group consisting of —H, —C₁-C₅ alkyl, —C₃-C₆cycloalkyl, —C₁-C₅ haloalkyl, aryl, heteroaryl, —(C═O)—C₀-C₈ alkyl, and—(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or where R₅ and R₆ selectedfrom these groups are combined to form a ring;

where R₄ is selected from the group consisting of —H, —O—R₅, —S—R₅, —F,—Cl, —Br, —I, and —NR₅R₆;

where X is selected from the group consisting of —H, —NR₇R₈, —OR₉ and—(CH₂)₂C(CH₃)₂OH;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁, and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

with the provisos that when n=3 and if R₄ is —H or —OH, then X is not—H, and that when R₁ and R₂ are —OMe and R₃ is -Me, then either R₄ isneither —H nor —OH, or X is neither —H nor —OH nor —(CH₂)₂C(CH₃)₂OH;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, R₁, R₂, and R₃ are independently selected fromthe group consisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —S—R₅,—CN, —F, —Cl, —Br, —I, —N₃, and —NR₅R₆. In another embodiment, R₁, R₂,and R₃ are independently selected from the group consisting of —H,—C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl,—C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —S—R₅, —CN, —F, —Cl, —Br, —I, —N₃,and —NR₅R₆; with the proviso that when R₁ is —C₁-C₅ alkyl and R₂ is —H,then R₃ is not —H. In another embodiment, R₁, R₂, and R₃ areindependently selected from —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl. Inanother embodiment, R₁, R₂ and R₃ are independently selected from —H,—C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl,—C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl; with the proviso that when R₁ is—C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl,—C₂-C₅ alkynyl, or —C₂-C₅ haloalkynyl and R₂ is —H, then R₃ is not —H.In another embodiment, at least one of R₁, R₂ and R₃ is independentlyselected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl. In anotherembodiment, n=0. In another embodiment, R₄ is —H or —OH. In anotherembodiment, the one or more compounds are selected from compounds of theformula:

or any stereoisomer, mixture of stereoisomers, pro drug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, at least two of R₁, R₂, and R₃ are independentlyselected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl. In anotherembodiment, R₁, R₂, and R₃ are independently selected from —C₂-C₅ alkyl,—C₂-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl,and —C₂-C₅ haloalkynyl. In another embodiment, X is —OH or —NH₂.

In another embodiment, the one or more compounds are selected fromcompounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, X is —(CH₂)₂C(CH₃)₂OH. In another embodiment, theone or more compounds are selected from compounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, R₄ is —H, —F, —Cl, —Br, —I, or —OH. In anotherembodiment, R₄ is —F, —Cl, or —I. In another embodiment, the one or morecompounds are selected from compounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, R₄ is —H, or —OH. In another embodiment, the oneor more compounds are selected from compounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In one embodiment, the invention embraces a method of treating amitochondrial disorder, modulating one or more energy biomarkers,normalizing one or more energy biomarkers, or enhancing one or moreenergy biomarkers, comprising administering to a subject atherapeutically effective amount or effective amount of one or morecompounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In any of the methods above, the compound or compounds to beadministered can be combined with a pharmaceutically acceptableexcipient.

In any of the methods above, the mitochondrial disorder can be selectedfrom the group consisting of inherited mitochondrial diseases; MyoclonicEpilepsy with Ragged Red Fibers (MERRF); Mitochondrial Myopathy,Encephalopathy, Lactacidosis, Stroke (MELAS); Leber's Hereditary OpticNeuropathy (LHON); Leigh Disease; Kearns-Sayre Syndrome (KSS);Friedreich's Ataxia (FA); other myopathies; cardiomyopathy;encephalomyopathy; renal tubular acidosis; neurodegenerative diseases;Parkinson's disease; Alzheimer's disease; amyotrophic lateral sclerosis(ALS); motor neuron diseases; other neurological diseases; epilepsy;genetic diseases; Huntington's Disease; mood disorders; schizophrenia;bipolar disorder; age-associated diseases; macular degeneration;diabetes; and cancer. In another embodiment, the mitochondrial disordercan be selected from the group consisting of inherited mitochondrialdiseases; Myoclonic Epilepsy with Ragged Red Fibers (MERRF);Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS);Leber's Hereditary Optic Neuropathy (LHON); Leigh Disease; Kearns-SayreSyndrome (KSS); and Friedreich's Ataxia (FA).

In any of the methods above for modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, the energy biomarker can be selected from thegroup consisting of: lactic acid (lactate) levels, either in wholeblood, plasma, cerebrospinal fluid, or cerebral ventricular fluid;pyruvic acid (pyruvate) levels, either in whole blood, plasma,cerebrospinal fluid, or cerebral ventricular fluid; lactate/pyruvateratios, either in whole blood, plasma, cerebrospinal fluid, or cerebralventricular fluid; phosphocreatine levels, NADH (NADH+H⁺) levels; NADPH(NADPH+H⁺) levels; NAD levels; NADP levels; ATP levels; reduced coenzymeQ (CoQ^(red)) levels; oxidized coenzyme Q (CoQ^(ox)) levels; totalcoenzyme Q (CoQ^(tot)) levels; oxidized cytochrome C levels; reducedcytochrome C levels; oxidized cytochrome C/reduced cytochrome C ratio;acetoacetate levels, β-hydroxy butyrate levels, acetoacetate/β-hydroxybutyrate ratio, 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels; levels ofreactive oxygen species; levels of oxygen consumption (VO2); levels ofcarbon dioxide output (VCO2); respiratory quotient (VCO2/VO2); exercisetolerance; and anaerobic threshold.

In any of the above methods, the subject can be selected from the groupconsisting of: a subject with a mitochondrial disease; a subjectundergoing strenuous or prolonged physical activity; a subject withchronic energy problems; a subject with chronic respiratory problems; apregnant female; a pregnant female in labor; a neonate; a prematureneonate; a subject exposed to an extreme environment; a subject exposedto a hot environment; a subject exposed to a cold environment; a subjectexposed to an environment with lower-than-average oxygen content; asubject exposed to an environment with higher-than-average carbondioxide content; a subject exposed to an environment withhigher-than-average levels of air pollution; a subject with lungdisease; a subject with lower-than-average lung capacity; a tubercularpatient; a lung cancer patient; an emphysema patient; a cystic fibrosispatient; a subject recovering from surgery; a subject recovering fromillness; a subject undergoing acute trauma; a subject in shock; asubject requiring acute oxygen administration; a subject requiringchronic oxygen administration; an elderly subject; an elderly subjectexperiencing decreased energy; and a subject suffering from chronicfatigue.

In another embodiment, the invention embraces compounds of the formula:

wherein the bond indicated with a dashed line can be single or double;

where R₁, R₂, and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —S—R₅, —CN, —F, —Cl,—Br, —I, —N₃, and —NR₅R₆, where at least one of R₁, R₂, and R₃ isindependently selected from —C₂-C₅ alkyl;

where R₅ and R₆ are independently selected from the group consisting of—H, —C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, heteroaryl,—(C═O)—C₀-C₈ alkyl, —(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or whereR₅ and R₆ selected from these groups are combined to form a ring;

where R₄ represents a linear or branched group containing 1 to 32 carbonatoms and any number of single, double, or triple bonds in anychemically possible combination;

where X is selected from the group consisting of —H, —F, —Cl, —Br, —I,—CN, —N₃, —NR₇R₈, and —OR₉;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁, and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ andR₂₁, together with the nitrogen atom to which they are attached combineto form a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, R₁, R₂, and R₃ are independently selected from —H—C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl,—C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl, and where at least one of R₁,R₂, and R₃ is independently selected from —C₂-C₅ alkyl, —C₂-C₅haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and—C₂-C₅ haloalkynyl. In another embodiment, at least one of R₁, R₂, andR₃ is independently selected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl; withthe proviso that X is not —H. In another embodiment, at least two of R₁,R₂, and R₃ are independently selected from —C₂-C₅ alkyl, —C₂-C₅haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅haloalkynyl. In another embodiment, R₁, R₂, and R₃ are independentlyselected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl.

In another embodiment, the invention embraces compounds of the formula:

wherein the bond indicated with a dashed line can be single or double;

where R₃ is selected from the group consisting of —H, —C₁-C₅ alkyl,—C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl,—C₂-C₅ haloalkynyl, —S—R₅, —CN, —F, —Cl, —Br, —I, —N₃, and —NR₅R₆; whereR₅ and R₆ are independently selected from the group consisting of —H,—C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, heteroaryl,—(C═O)—C₀-C₈ alkyl, —(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or whereR₅ and R₆ selected from these groups are combined to form a ring;

where R₄ represents a linear or branched group containing 1 to 32 carbonatoms and any number of single, double, or triple bonds in anychemically possible combination;

where X is selected from the group consisting of —F, —Cl, —Br, —I, —CN,—N₃, —NR₇R₈, and —OR₉;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁ and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₉ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁, whereR₂₀ is —(CH₂)_(p)—, R₂₁, is —(CH₂)_(q)—, p and q are independentlyintegers between 0 and 7 inclusive, p+q is between 2 and 7 inclusive,R₂₀ and R₂₁ together with the nitrogen atom to which they are attachedcombine to form a 3- to 8-membered ring, and where another groupselected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionallyincorporated in the ring formed by R₂₀ and R₂₁ and the nitrogen atom towhich they are attached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl,—S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, the one or more compounds are selected fromcompounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, the invention embraces compounds of the formula:

wherein the bond indicated with a dashed line can be single or double;

where R₁, R₂, and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —S—R₅, —CN, —F, —Cl,—Br, —I, —N₃, and —NR₅R₆; where R₅ and R₆ are independently selectedfrom the group consisting of —H, —C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅haloalkyl, aryl, heteroaryl, —(C═O)—C₀-C₈ alkyl, and —(C═O)—C₀-C₈alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or where R₅ and R₆ selected from thesegroups are combined to form a ring;

where R₄ is —(CH₂)_(n)C(CH₃)₂—, where n is an integer from 0 to 15inclusive;

where X is selected from the group consisting of —H, —F, —Cl, —Br, —I,—CN, —N₃, —NR₇R₈, and —OR₉;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁ and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁, is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ andR₂₁, together with the nitrogen atom to which they are attached combineto form a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, X is —H or —OH.

In another embodiment, the invention embraces compounds of the formula:

wherein the bond indicated with a dashed line can be single or double;

where R₁, R₂, and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —O—R₅, —S—R₅, —CN, —F,—Cl, —Br, —I, —N₃, and —NR₅R₆; where R₅ is independently selected fromgroup consisting of —C₂-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl,aryl, and heteroaryl, and R₆ is independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl,aryl, heteroaryl, —(C═O)—C₀-C₈ alkyl, and —(C═O)—C₀-C₈ alkyl-C₆-C₁₀aryl-C₀-C₈ alkyl, or where R₅ and R₆ selected from these groups arecombined to form a ring; with the proviso that at least one of R₁, R₂,and R₃ is —OR₅;

where R₄ represents a linear or branched group containing 1 to 32 carbonatoms and any number of single, double, or triple bonds in anychemically possible combination;

where X is selected from the group consisting of —H, —F, —Cl, —Br, —I,—CN, —N₃, —NR₇R₈, and —OR₉;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁, is —(CH₂)_(q)—, p and qare independently integers between 0 and 7 inclusive, p+q is between 2and 7 inclusive, R₂₀ and R₂₁ together with the nitrogen atom to whichthey are attached combine to form a 3- to 8-membered ring, and whereanother group selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁ and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, at least two of R₁, R₂, and R₃ are independentlyselected from —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl. In anotherembodiment, R₁, R₂, and R₃ are independently selected from —C₁-C₅ alkyl,—C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl,and —C₂-C₅ haloalkynyl.

In another embodiment, the invention embraces compounds of the formula:

wherein the bond indicated with a dashed line can be single or double;

where R₁, R₂, and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, —O—R₅, —S—R₅, —CN, —F,—Cl, —Br, —I, —N₃, and —NR₅R₆;

where R₅ is independently selected from group consisting of —H, —C₂-C₅alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, and heteroaryl, and R₆is independently selected from the group consisting of —H, —C₁-C₅ alkyl,—C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, heteroaryl, —(C═O)—C₀-C₈alkyl, and —(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or where R₅ andR₆ selected from these groups are combined to form a ring;

where R₄—(CH₂)_(n)C(CH₃)₂— where n is an integer from 0 to 15 inclusive;

where X is selected from the group consisting of —H, —F, —Cl, —Br, —I,—CN, —N₃, —NR₇R₈, and —OR₉;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁, together with the nitrogen atom to which theyare attached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁, and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, X is —H or —OH.

In another embodiment, the invention embraces compounds of the formula:

where n is an integer from 0 to 9 inclusive, and each unit can be thesame or different;

wherein the bonds indicated with dashed lines can be single or double;

wherein R₁, R₂ and R₃ are independently selected from —H, —C₁-C₅ alkyl,—C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl,—C₂-C₅ haloalkynyl, and wherein at least one of R₁, R₂, and R₃ isindependently selected from —C₂-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl, withthe proviso that when R₂ is —C₁-C₅ alkyl and R₁ is —H, then R₃ is not—H;

where R₄ is selected from the group consisting of —H, —O—R₅, —S—R₅, —F,—Cl, —Br, —I, and —NR₅R₆; where X is selected from the group consistingof —H, —NR₇R₈, —OR₉ and —(CH₂)₂C(CH₃)₂OH; where R₅ and R₆ areindependently selected from the group consisting of —H, —C₁-C₅ alkyl,—C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, heteroaryl, —(C═O)—C₀-C₈alkyl, and —(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or where R₅ andR₆ selected from these groups are combined to form a ring;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁ and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

with the provisos that when n=3 and R₄ is —H or —OH, then X is not —H,

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, n=0. In another embodiment, R₄ is —H or —OH. Inanother embodiment, the compound is of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, at least two of R₁, R₂, and R₃ are independentlyselected from —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅ haloalkynyl. In another embodiment,R₁, R₂, and R₃ are independently selected from —C₂-C₅ alkyl, —C₂-C₅haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, —C₂-C₅haloalkynyl.

In another embodiment, the invention embraces compounds of the formula:

where n is an integer from 0 to 9 inclusive, and each unit can be thesame or different;

wherein the bonds indicated with dashed lines can be single or double;

wherein R₁, R₂ and R₃ are independently selected from —H, —C₁-C₅ alkyl,—C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl,—C₂-C₅ haloalkynyl with the proviso that when R₂ is —C₁-C₅ alkyl and R₁is —H, then R₃ is not —H; where R₄ is selected from the group consistingof —H, —O—R₅, —S—R₅, —F, —Cl, —Br, —I, and —NR₅R₆; where X is selectedfrom the group consisting of —NR₇R₈, —OR₉ and —(CH₂)₂C(CH₃)₂OH;

where R₅ and R₆ are independently selected from the group consisting of—H, —C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅ haloalkyl, aryl, heteroaryl,—(C═O)—C₀-C₈ alkyl, and —(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, orwhere R₅ and R₆ selected from these groups are combined to form a ring;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁ and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

with the provisos that when R₁ and R₂ are —OMe and R₃ is -Me, theneither R₄ is neither —H nor —OH, or X is neither —OH nor—(CH₂)₂C(CH₃)₂OH;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, X is —OH or —NH₂.

In another embodiment, the one or more compounds are selected fromcompounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, X is —(CH₂)₂C(CH₃)₂OH. In another embodiment, thecompound is selected from

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, the invention embraces compounds of the formula:

where n is an integer from 0 to 9 inclusive, and each unit can be thesame or different;

wherein the bonds indicated with dashed lines can be single or double;

wherein R₁, R₂ and R₃ are independently selected from —H, —C₁-C₅ alkyl,—C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl,—C₂-C₅ haloalkynyl, with the proviso that when R₂ is —C₁-C₅ alkyl and R₁is —H, then R₃ is not —H;

where R₄ is selected from the group consisting of F, Cl, and I; where Xis selected from the group consisting of —H, —NR₇R₈, —OR₉, and—(CH₂)₂C(CH₃)₂OH; where R₅ and R₆ are independently selected from thegroup consisting of —H, —C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅haloalkyl, aryl, heteroaryl, —(C═O)—C₀-C₈ alkyl, and —(C═O)—C₀-C₈alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or where R₅ and R₆ selected from thesegroups are combined to form a ring;

where R₇ and R₈ are independently selected from —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl, —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈are independently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl, —(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl,—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₂₀ and R₂₁ and thenitrogen atom to which they are attached, —(C═O)—OC₁-C₈ alkyl,—(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈ alkyl, —S(O)₂ aryl, and —S(O)₂aralkyl, and where the other of R₇ or R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl or where R₇ and R₈ selected from these groups are combined toform a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₇ and R₈ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from —NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can beoptionally incorporated in the ring formed by R₇ and R₈ and the nitrogenatom to which they are attached;

where R₉ is independently selected from —H, —C₁-C₈ alkyl or —C₁-C₈haloalkyl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈ haloalkyl, —(C═O)—NH₂,—(C═O)—NHC₁-C₈ alkyl, —(C═O)—NHC₁-C₈ haloalkyl, —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from—NH—, —N(C₁-C₄ alkyl)-, —O—, or —S— can be optionally incorporated inthe ring formed by R₂₀ and R₂₁ and the nitrogen atom to which they areattached, —(C═O)—OC₁-C₈ alkyl, —(C═O)—OC₁-C₈ haloalkyl, —S(O)₂C₁-C₈alkyl, —S(O)₂ aryl, and —S(O)₂;

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, the compound is selected from

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

In another embodiment, the invention embraces compounds of the formula:

or any stereoisomer, mixture of stereoisomers, prodrug, metabolite,salt, phosphate-substituted form, sulfate-substituted form,phosphate/sulfate substituted form, crystalline form, non-crystallineform, hydrate, or solvate thereof.

For any of the compounds described above, the compound can be combinedwith a pharmaceutically acceptable excipient.

In another embodiment, the invention embraces a method of treating orsuppressing a mitochondrial disorder, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount or effective amount of one or more compounds as described above.

In another embodiment, the invention embraces a method of treating orsuppressing a mitochondrial disorder, modulating one or more energybiomarkers, normalizing one or more energy biomarkers, or enhancing oneor more energy biomarkers, by administering a therapeutically effectiveamount or effective amount of one or more of the compounds describedabove.

In other embodiments, including any of the foregoing embodiments, themitochondrial disorder is selected from the group consisting ofinherited mitochondrial diseases; Myoclonic Epilepsy with Ragged RedFibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis,Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); LeighDisease; Kearns-Sayre Syndrome (KSS); Friedreich's Ataxia (FA); othermyopathies; cardiomyopathy; encephalomyopathy; renal tubular acidosis;neurodegenerative diseases; Parkinson's disease; Alzheimer's disease;amyotrophic lateral sclerosis (ALS); motor neuron diseases; otherneurological diseases; epilepsy; genetic diseases; Huntington's Disease;mood disorders; schizophrenia; bipolar disorder; age-associateddiseases; macular degeneration; diabetes; and cancer.

In another embodiment, including any of the foregoing embodiments, themitochondrial disorder is selected from the group consisting ofinherited mitochondrial diseases; Myoclonic Epilepsy with Ragged RedFibers (MERRF); Mitochondrial Myopathy, Encephalopathy, Lactacidosis,Stroke (MELAS); Leber's Hereditary Optic Neuropathy (LHON); LeighDisease; Keams-Sayre Syndrome (KSS); and Friedreich's Ataxia (FA).

In another embodiment of the invention, including any of the foregoingembodiments, the mitochondrial disorder is Friedreich's ataxia (FRDA).In another embodiment of the invention, the mitochondrial disorder isLeber's Hereditary Optic Neuropathy (LHON). In another embodiment of theinvention, the mitochondrial disorder is mitochondrial myopathy,encephalopathy, lactacidosis, stroke (MELAS). In another embodiment ofthe invention, the mitochondrial disorder is Kearns-Sayre Syndrome(KSS). In another embodiment of the invention, the mitochondrialdisorder is Myoclonic Epilepsy with Ragged Red Fibers (MERRF). Inanother embodiment of the invention, the mitochondrial disorder isParkinson's disease.

In another embodiment of the invention, including any of the foregoingembodiments, the compounds described herein are administered to subjectssuffering from a mitochondrial disorder to modulate one or more ofvarious energy biomarkers, including, but not limited to, lactic acid(lactate) levels, either in whole blood, plasma, cerebrospinal fluid, orcerebral ventricular fluid; pyruvic acid (pyruvate) levels, either inwhole blood, plasma, cerebrospinal fluid, or cerebral ventricular fluid;lactate/pyruvate ratios, either in whole blood, plasma, cerebrospinalfluid, or cerebral ventricular fluid; phosphocreatine levels, NADH(NADH+H⁺) or NADPH (NADPH+H⁺) levels; NAD or NADP levels; ATP levels;reduced coenzyme Q (CoQ^(red)) levels; oxidized coenzyme Q (CoQ^(ox))levels; total coenzyme Q (CoQ^(tot)) levels; oxidized cytochrome Clevels; reduced cytochrome C levels; oxidized cytochrome C/reducedcytochrome C ratio; acetoacetate levels; beta-hydroxy butyrate levels;acetoacetate/beta-hydroxy butyrate ratio; 8-hydroxy-2′-deoxyguanosine(8-OHdG) levels; levels of reactive oxygen species; oxygen consumption(VO2), carbon dioxide output (VCO2), respiratory quotient (VCO2/VO2),and to modulate exercise intolerance (or conversely, modulate exercisetolerance) and to modulate anaerobic threshold. Energy biomarkers can bemeasured in whole blood, plasma, cerebrospinal fluid, cerebroventricularfluid, arterial blood, venous blood, or any other body fluid, body gas,or other biological sample useful for such measurement. In oneembodiment, the levels are modulated to a value within about 2 standarddeviations of the value in a healthy subject. In another embodiment, thelevels are modulated to a value within about 1 standard deviation of thevalue in a healthy subject. In another embodiment, the levels in asubject are changed by at least about 10% above or below the level inthe subject prior to modulation. In another embodiment, the levels arechanged by at least about 20% above or below the level in the subjectprior to modulation. In another embodiment, the levels are changed by atleast about 30% above or below the level in the subject prior tomodulation. In another embodiment, the levels are changed by at leastabout 40% above or below the level in the subject prior to modulation.In another embodiment, the levels are changed by at least about 50%above or below the level in the subject prior to modulation. In anotherembodiment, the levels are changed by at least about 75% above or belowthe level in the subject prior to modulation. In another embodiment, thelevels are changed by at least about 100% above or at least about 90%below the level in the subject prior to modulation.

In another embodiment, including any of the foregoing embodiments, thesubject or subjects in which a method of treating or suppressing amitochondrial disorder, modulating one or more energy biomarkers,normalizing one or more energy biomarkers, or enhancing one or moreenergy biomarkers is performed is/are selected from the group consistingof subjects undergoing strenuous or prolonged physical activity;subjects with chronic energy problems; subjects with chronic respiratoryproblems; pregnant females; pregnant females in labor; neonates;premature neonates; subjects exposed to extreme environments; subjectsexposed to hot environments; subjects exposed to cold environments;subjects exposed to environments with lower-than-average oxygen content;subjects exposed to environments with higher-than-average carbon dioxidecontent; subjects exposed to environments with higher-than-averagelevels of air pollution; airline travelers; flight attendants; subjectsat elevated altitudes; subjects living in cities with lower-than-averageair quality; subjects working in enclosed environments where air qualityis degraded; subjects with lung diseases; subjects withlower-than-average lung capacity; tubercular patients; lung cancerpatients; emphysema patients; cystic fibrosis patients; subjectsrecovering from surgery; subjects recovering from illness; elderlysubjects; elderly subjects experiencing decreased energy; subjectssuffering from chronic fatigue; subjects suffering from chronic fatiguesyndrome; subjects undergoing acute trauma; subjects in shock; subjectsrequiring acute oxygen administration; subjects requiring chronic oxygenadministration; or other subjects with acute, chronic, or ongoing energydemands who can benefit from enhancement of energy biomarkers.

In another embodiment, the invention embraces one or more compoundsdescribed herein in combination with a pharmaceutically acceptableexcipient, carrier, or vehicle.

In another embodiment, the invention embraces the use of one or morecompounds described herein in therapy. In another embodiment, theinvention embraces the use of one or more compounds described herein inthe therapy of mitochondrial disease. In another embodiment, theinvention embraces the use of one or more compounds described herein inthe manufacture of a medicament for use in therapy of mitochondrialdisease.

For all of the compounds and methods described above, the quinone formcan also be used in its reduced (hydroquinone) form when desired.Likewise, the hydroquinone form can also be used in its oxidized(quinone) form when desired.

For all of the compounds and methods described above, R₁, R₂, and R₃,when present, can be selected from the group consisting of H and C₁-C₅alkyl, or from C₁-C₅ alkyl.

MODES FOR CARRYING OUT THE INVENTION

The invention embraces compounds useful in treating or suppressingmitochondrial disorders, and methods of using such compounds formodulation of energy biomarkers. The redox active therapeutics fortreatment or suppression of mitochondrial diseases and associatedaspects of the invention are described in more detail herein.

By “subject,” “individual,” or “patient” is meant an individualorganism, preferably a vertebrate, more preferably a mammal, mostpreferably a human.

“Treating” a disease with the compounds and methods discussed herein isdefined as administering one or more of the compounds discussed herein,with or without additional therapeutic agents, in order to reduce oreliminate either the disease or one or more symptoms of the disease, orto retard the progression of the disease or of one or more symptoms ofthe disease, or to reduce the severity of the disease or of one or moresymptoms of the disease. “Suppression” of a disease with the compoundsand methods discussed herein is defined as administering one or more ofthe compounds discussed herein, with or without additional therapeuticagents, in order to suppress the clinical manifestation of the disease,or to suppress the manifestation of adverse symptoms of the disease. Thedistinction between treatment and suppression is that treatment occursafter adverse symptoms of the disease are manifest in a subject, whilesuppression occurs before adverse symptoms of the disease are manifestin a subject. Suppression may be partial, substantially total, or total.Because many of the mitochondrial disorders are inherited, geneticscreening can be used to identify patients at risk of the disease. Thecompounds and methods of the invention can then be administered toasymptomatic patients at risk of developing the clinical symptoms of thedisease, in order to suppress the appearance of any adverse symptoms.“Therapeutic use” of the compounds discussed herein is defined as usingone or more of the compounds discussed herein to treat or suppress adisease, as defined above. An “effective amount” of a compound is anamount of the compound sufficient to modulate, normalize, or enhance oneor more energy biomarkers (where modulation, normalization, andenhancement are defined below). A “therapeutically effective amount” ofa compound is an amount of the compound, which, when administered to asubject, is sufficient to reduce or eliminate either a disease or one ormore symptoms of a disease, or to retard the progression of a disease orof one or more symptoms of a disease, or to reduce the severity of adisease or of one or more symptoms of a disease, or to suppress theclinical manifestation of a disease, or to suppress the manifestation ofadverse symptoms of a disease. A therapeutically effective amount can begiven in one or more administrations. An “effective amount” of acompound embraces both a therapeutically effective amount, as well as anamount effective to modulate, normalize, or enhance one or more energybiomarkers in a subject.

“Modulation” of, or to “modulate,” an energy biomarker means to changethe level of the energy biomarker towards a desired value, or to changethe level of the energy biomarker in a desired direction (e.g., increaseor decrease). Modulation can include, but is not limited to,normalization and enhancement as defined below.

“Normalization” of, or to “normalize,” an energy biomarker is defined aschanging the level of the energy biomarker from a pathological valuetowards a normal value, where the normal value of the energy biomarkercan be 1) the level of the energy biomarker in a healthy person orsubject, or 2) a level of the energy biomarker that alleviates one ormore undesirable symptoms in the person or subject. That is, tonormalize an energy biomarker which is depressed in a disease statemeans to increase the level of the energy biomarker towards the normal(healthy) value or towards a value which alleviates an undesirablesymptom; to normalize an energy biomarker which is elevated in a diseasestate means to decrease the level of the energy biomarker towards thenormal (healthy) value or towards a value which alleviates anundesirable symptom.

“Enhancement” of, or to “enhance,” energy biomarkers means tointentionally change the level of one or more energy biomarkers awayfrom either the normal value, or the value before enhancement, in orderto achieve a beneficial or desired effect. For example, in a situationwhere significant energy demands are placed on a subject, it may bedesirable to increase the level of ATP in that subject to a level abovethe normal level of ATP in that subject. Enhancement can also be ofbeneficial effect in a subject suffering from a disease or pathologysuch as a mitochondrial disease, in that normalizing an energy biomarkermay not achieve the optimum outcome for the subject; in such cases,enhancement of one or more energy biomarkers can be beneficial, forexample, higher-than-normal levels of ATP, or lower-than-normal levelsof lactic acid (lactate) can be beneficial to such a subject.

By modulating, normalizing, or enhancing the energy biomarker Coenzyme Qis meant modulating, normalizing, or enhancing the variant or variantsof Coenzyme Q which is predominant in the species of interest. Forexample, the variant of Coenzyme Q which predominates in humans isCoenzyme Q10. If a species or subject has more than one variant ofCoenzyme Q present in significant amounts (i.e., present in amountswhich, when modulated, normalized, or enhanced, can have a beneficialeffect on the species or subject), modulating, normalizing, or enhancingCoenzyme Q can refer to modulating, normalizing or enhancing any or allvariants of Coenzyme Q present in the species or subject.

While the compounds described herein can occur and can be used as theneutral (non-salt) compound, the description is intended to embrace allsalts of the compounds described herein, as well as methods of usingsuch salts of the compounds. In one embodiment, the salts of thecompounds comprise pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts are those salts which can be administered as drugs orpharmaceuticals to humans and/or animals and which, upon administration,retain at least some of the biological activity of the free compound(neutral compound or non-salt compound). The desired salt of a basiccompound may be prepared by methods known to those of skill in the artby treating the compound with an acid. Examples of inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, and phosphoric acid. Examples of organicacids include, but are not limited to, formic acid, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, andsalicylic acid. Salts of basic compounds with amino acids, such asaspartate salts and glutamate salts, can also be prepared. The desiredsalt of an acidic compound can be prepared by methods known to those ofskill in the art by treating the compound with a base. Examples ofinorganic salts of acid compounds include, but are not limited to,alkali metal and alkaline earth salts, such as sodium salts, potassiumsalts, magnesium salts, and calcium salts; ammonium salts; and aluminumsalts. Examples of organic salts of acid compounds include, but are notlimited to, procaine, dibenzylamine, N-ethylpiperidine,N,N′-dibenzylethylenediamine, and triethylamine salts. Salts of acidiccompounds with amino acids, such as lysine salts, can also be prepared.

The invention also includes all stereoisomers and geometric isomers ofthe compounds, including diastereomers, enantiomers, and cis/trans (E/Z)isomers. The invention also includes mixtures of stereoisomers and/orgeometric isomers in any ratio, including, but not limited to, racemicmixtures.

The compounds can be administered in prodrug form. Prodrugs arederivatives of the compounds which are themselves relatively inactive,but which convert into the active compound when introduced into thesubject in which they are used, by a chemical or biological process invivo, such as an enzymatic conversion. Suitable prodrug formulationsinclude, but are not limited to, peptide conjugates of the compounds ofthe invention and esters of compounds of the inventions. Furtherdiscussion of suitable prodrugs is provided in H. Bundgaard, Design ofProdrugs, New York: Elsevier, 1985; in R. Silverman, The OrganicChemistry of Drug Design and Drug Action, Boston: Elsevier, 2004; in R.L. Juliano (ed.), Biological Approaches to the Controlled Delivery ofDrugs (Annals of the New York Academy of Sciences, v. 507), New York:N.Y. Academy of Sciences, 1987; and in E. B. Roche (ed.), Design ofBiopharmaceutical Properties Through Prodrugs and Analogs (Symposiumsponsored by Medicinal Chemistry Section, APhA Academy of PharmaceuticalSciences, November 1976 national meeting, Orlando, Fla.), Washington:The Academy, 1977.

The invention includes derivatives of compounds described hereinsubstituted with one or more phosphate groups and/or sulfate groups. Acompound is “phosphate-substituted” when it contains one or morephosphate groups and is “sulfate-substituted” when it contains one ormore sulfate groups. A “phosphate/sulfate substituted” compound containsat least one phosphate and at least one sulfate group. For example, oneor more hydroxyl groups of a phenyl ring may be substituted to form acompound such as:

wherein R₁, R₂, and R₃ are as described herein and where R₁₀₀ and R₂₀₀can be independently selected from —H, —PO₃ ²⁻, and —SO₃ ⁻. In oneembodiment, the invention embraces compounds where R₁₀₀ is —H and R₂₀₀is —PO₃ ²⁻. In another embodiment, the invention embraces compoundswhere R₁₀₀ is —H and R₂₀₀ is —SO₃ ⁻. In another embodiment, theinvention embraces compounds where R₁₀₀ is —SO₃ ⁻ and R₂₀₀ is —PO₃ ²⁻.In another embodiment, the invention embraces compounds where R₁₀₀ is—PO₃ ²⁻ and R₂₀₀ is —SO₃ ⁻. In another embodiment, the inventionembraces compounds where R₁₀₀ is —PO₃ ²⁻ and R₂₀₀ is —H. In anotherembodiment, the invention embraces compounds where R₁₀₀ is —SO₃ ⁻ andR₂₀₀ is —H. In another embodiment, the invention embraces compoundswhere R₁₀₀ and R₂₀₀ are —PO₃ ²⁻. In another embodiment, the inventionembraces compounds where R₁₀₀ and R₂₀₀ are —SO₃ ⁻. Additionally includedin this invention are all protonated or partially protonated forms andsalts thereof of compounds substituted with phosphates and/or sulfates.

The various compounds of the invention can be administered either astherapeutic agents in and of themselves, or as prodrugs which willconvert to other therapeutically effective or effective substances inthe body.

Metabolites of the compounds are also embraced by the invention.However, metabolites of substances which occur naturally in subjects areexcluded from the claimed compounds of the invention.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain, cyclic groups, and combinations thereof,having the number of carbon atoms specified, or if no number isspecified, having up to 12 carbon atoms. “Straight-chain alkyl” or“linear alkyl” groups refers to alkyl groups that are neither cyclic norbranched, commonly designated as “n-alkyl” groups. Examples of alkylgroups include, but are not limited to, groups such as methyl, ethyl,n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl,pentyl, n-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andadamantyl. Cycloalkyl groups can consist of one ring, including, but notlimited to, groups such as cycloheptyl, or multiple fused rings,including, but not limited to, groups such as adamantyl or norbornyl.One preferred subset of alkyl groups is C₁-C₅ alkyl, which is intendedto embrace methyl (Me), ethyl (Et), propyl (Pr), n-propyl (nPr),isopropyl (iPr), butyl (Bu), n-butyl (nBu), isobutyl (iBu), sec-butyl(sBu), t-butyl (tBu), cyclopropyl (cyclPr), cyclobutyl (cyclBu),cyclopropyl-methyl (cyclPr-Me), methyl-cyclopropane (Me-cyclPr), pentyl,n-pentyl, isopentyl, neopentyl, sec-pentyl, t-pentyl,1,2-dimethylpropyl, cyclopentyl, and any other alkyl group containingbetween one and five carbon atoms, where the C₁-C₅ alkyl groups can beattached via any valence on the C₁-C₅ alkyl groups.

Note that “C₀ alkyl,” when it appears, is intended to mean either anon-existent group, or a hydrogen, which will be understood by thecontext in which it appears. When a C₀ alkyl group appears as theterminal group on a chain, as for example in —(C═O)—C₀ alkyl, it isintended as a hydrogen atom; thus, —(C═O)—C₀ alkyl is intended torepresent —(C═O)—H (an aldehyde). When a C₀ alkyl group appears betweentwo other groups, as, for example, in —(C═O)—C₀ alkyl-C₆-C₁₀ aryl, it isintended to be a nonentity, thus —(C═O)—C₀ alkyl-C₆-C₁₀ aryl represents—(C═O)—C₆-C₁₀ aryl.

“Substituted alkyl” refers to alkyl groups substituted with one or moresubstituents including, but not limited to, groups such as halogen(fluoro, chloro, bromo, and iodo), alkoxy, acyloxy, amino, hydroxyl,mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy,carboxaldehyde, carboalkoxy and carboxamide, or a functionality that canbe suitably blocked, if necessary for purposes of the invention, with aprotecting group. Examples of substituted alkyl groups include, but arenot limited to, groups such as —CH₂—OH; —CH₂CH₂CH(NH₂)CH₃, etc. Thesubstituent(s) on the substituted alkyl group may be at any availablelocation on the group. Substituted alkyl embraces the preferred subsetof C₁-C₅ haloalkyl, which is intended to embrace any C₁-C₅ alkylsubstituent having at least one halogen substituent; the halogen can beattached via any available valence on the C₁-C₅ alkyl group. One furthersubset of C₁-C₅ haloalkyl is —CF₃, —CCl₃, —CBr₃, and —CI₃. Anotherfurther subset of C₁-C₅ haloalkyl is the subset with exactly one halogensubstituent. Another further subset of C₁-C₅ haloalkyl is the subsetwith exactly one chloro substituent. Another further subset of C₁-C₅haloalkyl is the subset with exactly one fluoro substituent. Anotherfurther subset of C₁-C₅ haloalkyl is the subset of C₁-C₅ perhaloalkyl;that is, C₁-C₅ alkyl with all available valences replaced by halogens.Another further subset of C₁-C₅ haloalkyl is the subset of C₁-C₅perfluoroalkyl; that is, C₁-C₅ alkyl with all available valencesreplaced by fluorines, such as —CF₃ and —CF₂—CF₃. Another further subsetof C₁-C₅ haloalkyl is the subset of C₁-C₅ perchloroalkyl; that is, C₁-C₅alkyl with all available valences replaced by chlorines.

The term “alkenyl” refers to unsaturated aliphatic groups includingstraight-chain (linear), branched-chain, cyclic groups, and combinationsthereof, having the number of carbon atoms specified, or if no number isspecified, having up to 12 carbon atoms, which contain at least onedouble bond (—C═C—). All double bonds may be independently either (E) or(Z) geometry, as well as arbitrary mixtures thereof. Examples of alkenylgroups include, but are not limited to, —CH₂—CH═CH—CH₃; and—CH₂—CH₂-cyclohexenyl, where the ethyl group can be attached to thecyclohexenyl moiety at any available carbon valence.

“Haloalkenyl” embraces any C₁-C₅ alkenyl substituent having at least onehalogen substituent; the halogen can be attached via any availablevalence on the C₁-C₅ alkenyl group. One further subset of C₁-C₅haloalkenyl is the subset with exactly one halogen substituent. Anotherfurther subset of C₁-C₅ haloalkenyl is the subset with exactly onechloro substituent. Another further subset of C₁-C₅ haloalkenyl is thesubset with exactly one fluoro substituent. Another further subset ofC₁-C₅ haloalkenyl is the subset of C₁-C₅ perhaloalkenyl; that is, C₁-C₅alkenyl with all available valences replaced by halogens. Anotherfurther subset of C₁-C₅ haloalkenyl is the subset of C₁-C₅perfluoroalkenyl; that is, C₁-C₅ alkenyl with all available valencesreplaced by fluorines. Another further subset of C₁-C₅ haloalkenyl isthe subset of C₁-C₅ perchloroalkenyl; that is, C₁-C₅ alkenyl with allavailable valences replaced by chlorines.

The term “alkynyl” refers to unsaturated aliphatic groups includingstraight-chain (linear), branched-chain, cyclic groups, and combinationsthereof, having the number of carbon atoms specified, or if no number isspecified, having up to 12 carbon atoms, which contain at least onetriple bond (—C≡C—). “Hydrocarbon chain” or “hydrocarbyl” refers to anycombination of straight-chain, branched-chain, or cyclic alkyl, alkenyl,or alkynyl groups, and any combination thereof. “Substituted alkenyl,”“substituted alkynyl,” and “substituted hydrocarbon chain” or“substituted hydrocarbyl” refer to the respective group substituted withone or more substituents, including, but not limited to, groups such ashalogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy,phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxyand carboxamide, or a functionality that can be suitably blocked, ifnecessary for purposes of the invention, with a protecting group.

“Haloalkynyl” embraces any C₁-C₅ alkynyl substituent having at least onehalogen substituent; the halogen can be attached via any availablevalence on the C₁-C₅ alkynyl group. One further subset of C₁-C₅haloalkynyl is the subset with exactly one halogen substituent. Anotherfurther subset of C₁-C₅ haloalkynyl is the subset with exactly onechloro substituent. Another further subset of C₁-C₅ haloalkynyl is thesubset with exactly one fluoro substituent. Another further subset ofC₁-C₅ haloalkynyl is the subset of C₁-C₅ perhaloalkynyl; that is, C₁-C₅alkynyl with all available valences replaced by halogens. Anotherfurther subset of C₁-C₅ haloalkynyl is the subset of C₁-C₅perfluoroalkynyl; that is, C₁-C₅ alkynyl with all available valencesreplaced by fluorines. Another further subset of C₁-C₅ haloalkynyl isthe subset of C₁-C₅ perchloroalkynyl; that is, C₁-C₅ alkynyl with allavailable valences replaced by chlorines.

“Aryl” or “Ar” refers to an aromatic group having a single ring(including, but not limited to, groups such as phenyl) or two or morecondensed rings (including, but not limited to, groups such as naphthylor anthryl), and includes both unsubstituted and substituted arylgroups. Aryls, unless otherwise specified, contain from 6 to 12 carbonatoms in the ring portion. A preferred range for aryls is from 6 to 10carbon atoms in the ring portion. “Substituted aryls” refers to arylssubstituted with one or more substituents, including, but not limitedto, groups such as alkyl, alkenyl, alkynyl, hydrocarbon chains, halogen,alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl,benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy andcarboxamide, or a functionality that can be suitably blocked, ifnecessary for purposes of the invention, with a protecting group.“Aralkyl” designates an alkyl-substituted aryl group, where any aryl canattached to the alkyl; the alkyl portion is a straight or branched chainof 1 to 6 carbon atoms, preferably the alkyl chain contains 1 to 3carbon atoms. When an aralkyl group is indicated as a substituent, thearalkyl group can be connected to the remainder of the molecule at anyavailable valence on either its alkyl moiety or aryl moiety; e.g., thetolyl aralkyl group can be connected to the remainder of the molecule byreplacing any of the five hydrogens on the aromatic ring moiety with theremainder of the molecule, or by replacing one of the alpha-hydrogens onthe methyl moiety with the remainder of the molecule. Preferably, thearalkyl group is connected to the remainder of the molecule via thealkyl moiety.

A preferred aryl group is phenyl, which can be substituted orunsubstituted. Examples of substituents for substituted phenyl groupsinclude, but are not limited to, alkyl, halogen (chlorine (—Cl), bromine(—Br), iodine (—I), or fluorine (—F)), hydroxy (—OH), or alkoxy (such asmethoxy, ethoxy, n-propoxy or i-propoxy, n-butoxy, i-butoxy, sec-butoxy,or tert-butoxy). Substituted phenyl groups preferably have one or twosubstituents; more preferably, one substituent.

“Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to alkyl,alkenyl, and alkynyl groups, respectively, that contain the number ofcarbon atoms specified (or if no number is specified, having up to 12carbon atoms) which contain one or more heteroatoms as part of the main,branched, or cyclic chains in the group. Heteroatoms include, but arenot limited to, N, S, O, and P; N and O are preferred. Heteroalkyl,heteroalkenyl, and heteroalkynyl groups may be attached to the remainderof the molecule either at a heteroatom (if a valence is available) or ata carbon atom. Examples of heteroalkyl groups include, but are notlimited to, groups such as —O—CH₃, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—S—CH₂—CH₂—CH₃, —CH₂—CH(CH₃)—S—CH₃, —CH₂—CH₂—NH—CH₂—CH₂—,1-ethyl-6-propylpiperidino, and morpholino. Examples of heteroalkenylgroups include, but are not limited to, groups such as—CH═CH—NH—CH(CH₃)—CH₂—. “Heteroaryl” or “HetAr” refers to an aromaticgroup having a single ring (including, but not limited to, examples suchas pyridyl, imidazolyl, thiophene, or furyl) or two or more condensedrings (including, but not limited to, examples such as indolizinyl orbenzothienyl) and having at least one hetero atom, including, but notlimited to, heteroatoms such as N, O, P, or S, within the ring. Unlessotherwise specified, heteroalkyl, heteroalkenyl, heteroalkynyl, andheteroaryl groups have between one and five heteroatoms and between oneand twelve carbon atoms. “Substituted heteroalkyl,” “substitutedheteroalkenyl,” “substituted heteroalkynyl,” and “substitutedheteroaryl” groups refer to heteroalkyl, heteroalkenyl, heteroalkynyl,and heteroaryl groups substituted with one or more substituents,including, but not limited to, groups such as alkyl, alkenyl, alkynyl,benzyl, hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl,mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy,carboxaldehyde, carboalkoxy and carboxamide, or a functionality that canbe suitably blocked, if necessary for purposes of the invention, with aprotecting group. Examples of such substituted heteroalkyl groupsinclude, but are not limited to, piperazine, substituted at a nitrogenor carbon by a phenyl or benzyl group, and attached to the remainder ofthe molecule by any available valence on a carbon or nitrogen,—NH—SO₂-phenyl, —NH—(C═O)O-alkyl, —NH—(C═O)O-alkyl-aryl, and—NH—(C═O)-alkyl. If chemically possible, the heteroatom(s) and/or thecarbon atoms of the group can be substituted. The heteroatom(s) can alsobe in oxidized form, if chemically possible.

The term “alkoxy” as used herein refers to an alkyl, alkenyl, alkynyl,or hydrocarbon chain linked to an oxygen atom and having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. Examples of alkoxy groups include, but are not limited to,groups such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy ori-propoxy), and butoxy (either n-butoxy, i-butoxy, sec-butoxy, ortert-butoxy). The groups listed in the preceding sentence are preferredalkoxy groups; a particularly preferred alkoxy substituent is methoxy.

The terms “halo” and “halogen” as used herein refer to the Group VIIaelements (Group 17 elements in the 1990 IUPAC Periodic Table, IUPACNomenclature of Inorganic Chemistry, Recommendations 1990) and includeCl, Br, F and I substituents. Preferred halogen substituents are Cl andF.

When fragments, such as alkyl fragments, heteroaryl fragments, etc., areindicated as substituents, the substituent fragment can be attached tothe remainder of the molecule at any point on the fragment wherechemically possible (i.e., by using any available valence at a givenpoint of the fragment, such as a valence made available by removing oneor more hydrogen atoms from the fragment) unless otherwise specified.For example, in the fragment —(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl,if the leftmost C₀-C₈ alkyl group is a C₃ alkyl group, it can beattached to the sp² carbon of the carbonyl group at any of the threecarbon atoms in the chain, unless otherwise specified. Likewise, theC₆-C₁₀ aryl group can be attached to the alkyl groups at any carbons inthe aryl group, unless otherwise specified.

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: 1) reacts selectively with the desiredfunctionality in good yield to give a protected substrate that is stableto the projected reactions for which protection is desired; 2) isselectively removable from the protected substrate to yield the desiredfunctionality; and 3) is removable in good yield by reagents compatiblewith the other functional group(s) present or generated in suchprojected reactions. Examples of suitable protecting groups can be foundin Greene et al. (1991) Protective Groups in Organic Synthesis, 3rd Ed.(John Wiley & Sons, Inc., New York). Amino protecting groups include,but are not limited to, mesitylenesulfonyl (Mts), benzyloxycarbonyl (CBzor Z), t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS or TBDMS),9-fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridylsulfonyl, or suitable photolabile protecting groups such as6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl,pyrenylmethoxycarbonyl, nitrobenzyl,α-,α-dimethyl-dimethoxybenzyloxycarbonyl (DDZ),5-bromo-7-nitroindolinyl, and the like. Hydroxyl protecting groupsinclude, but are not limited to, Fmoc, TBS, photolabile protectinggroups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxymethyl ether), and Mem (methoxy ethoxy methyl ether), NPEOC(4-nitrophenethyloxycarbonyl) and NPEOM(4-nitrophenethyloxymethyloxycarbonyl).

Synthesis of Compounds

The compounds of the invention can be readily synthesized by a varietyof methods. Suitable protecting groups for reactions described hereinare detailed in the text by Theodora W. Greene and Peter G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, Hoboken, N.J.:Wiley-Interscience, 1999. The syntheses below are illustrated with R₁,R₂, and R₃ as methyl; however, the methods are generally applicable whenR₁, R₂, and R₃ are selected from other substituents, with suitableprotection if necessary.

A method of synthesizing compounds of formula I is by adapting thefollowing synthesis for the compound 1:

which is as follows:

where hydroquinone 2 is dissolved in ethanol and treated with a basicsolution of Me₂SO₄. Acidic workup and column chromatography yield thedimethyoxy protected hydroquinone 3. The chloromethyl group isintroduced by dissolving 3 into a solution of concentrated HCl andparaformaldehyde while adding HCl gas. Neutralization and isolationprovide the product 4. Cross-coupling according to the method outlinedin Lipshutz, B. H. et. al. J. Am. Chem. Soc. 1996, 118, 5512-5513 yieldsthe E-allylated aromatic species 5. Compound 5 is reduced by Pd/Ccatalyzed hydrogenation in an appropriate solvent such as EtOH, MeOH, orEtOAc to give a racemic mixture of reduced products 6. The protectedhydroquinone is then oxidized to the quinone by treatment with CAN inacetonitrile/water mixtures to give 1,4-benzoquinone 7 directly andsubsequently reduced to hydroquinone 1 by treatment of a biphasicmixutre of an etherial solvent with a basic aqueous solution of Na₂S₂O₄(Vogel, A. I. et. al. Vogel's Textbook of Practical Organic Chemistry,5th Edition, Prentice Hall: New York, 1996). Standard workup in theabsence of oxygen yields the desired hydroquinone. Single enantiomersare available by substituting the appropriate chiral hydrogenationcatalyst (Bell, S. et. al. Science 2006, 311, 642-644) in place of Pd/C.

Another method of making compounds of formula I is by adapting thefollowing synthesis of compound 8 of the form:

where precursor 5, prepared as for compound 1, is oxidized to thequinone 8 by treated with CAN in acetonitrile/water. Alternatively,quinone 8 can be prepared directly by coupling with2-chloromethyl-3,5,6-trimethy-[1,4]-benzoquinone as described inLipshutz, B. H. et al. Tetrahedron 1998, 54, 1241-1253.

Another method of making compounds of formula I is by adapting thefollowing synthesis of compound 9 of the form:

which is as follows:

where hydroquinone 10 is methylated using methyliodide to give 11, whichis subsequently chloromethylated to provide benzylic chloride 12. Thisis cross-coupled with the appropriate vinyl alane to give 13. Compound13 is oxidized using CAN in acetonitrile/water to provide quinone 14,which is then exhaustively reduced by treatment with hydrogen andcatalytic palladium on carbon to give hydroquinone. 15. Compound 15 isthen oxidized to quinone 9 by exposure to atmospheric oxygen in thepresence of silica gel. Alternatively, quinone 14 can be prepareddirectly by coupling with2-chloromethyl-3-tertbutyl-5,6-dimethy-[1,4]-benzoquinone as describedin Lipshutz, B. H. et al. Tetrahedron 1998, 54, 1241-1253.

Another method of making compounds of formula I is by adapting thefollowing synthesis of compound 16 of the form:

where precursor 14, prepared as with compound 9, is converted to thecorresponding hydroquinone 16 by reduction with tin tetrachloride.

A method of synthesizing compounds of formula II is by adapting thefollowing synthesis for the compound 17:

which is as follows:

where 2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol isprepared as described by Walkinshaw, et al., US 2005/0065099 A1, Mar.24, 2005. Oxidation by treatment with CAN yields the correspondingquinone, which can be exhaustively reduced, followed by reoxidation, togive compound 17.

Another method of making compounds of formula II is by adapting thefollowing synthesis of compound 23 of the form:

which is as follows:

where 2,3-dimethy-[1,4]-benzoquinone, prepared by ferric chlorideoxidation of 2,3-dimethyl-benzene-1,4-diol, is coupled with 4-methylpentanoic acid via oxidative decarboxylation mediated by persulfate andsilver nitrate to give compound 23 directly.

Another method of making compounds of formula II is by adapting thefollowing synthesis of compound 27 of the form:

which is as follows:

where alpha tocotrienol quinone 28 is selectively oxidized withtert-butylhydrogenperoxide and catalytic selenium dioxide according toTet. Lett. 1989, 30(29), 3749-3752 to give allylic alcohol 29. Alcohol29 is converted to its tosylate using tosyl chloride and pyridine togive 30. Tosylate 30 is displaced using sodium azide in refluxingethanol to give 31. Azide 31 is reduced selectively usingtriphenylphosphine to give amine 27.

Another method of making compounds of formula II is by adapting thefollowing synthesis of compound 32 of the form:

where precursor azide 31, prepared as with compound 27, is treated withhydrogen and catalytic palladium on carbon followed by reoxidation byexposure to atmospheric oxygen in the presence of catalytic SiO₂ to givethe desired amine.

Another method of making compounds of formula II is by adapting thefollowing synthesis of compound 33 of the form:

which is as follows:

where alpha tocotrienol quinone 28 is selectively hydrobrominated at theterminal olefin according to the procedure described in J. Am. Chem.Soc. 2005, 127(42), 14911-14921. This intermediate is then cyclized toform epoxide 34 by treatment with potassium carbonate. Epoxide 34 isselectively opened using CdCl₂/Mg to give tertiary alcohol 35 accordingto the procedure in Tet. Lett. 1993, 34(10), 1681-1684, which isre-oxidized by exposure to atmospheric oxygen in the presence ofcatalytic SiO₂ to give quinone 36. The remaining olefins are reducedusing hydrogen and catalytic palladium on carbon to give 37, which isre-oxidized to quinone 33 by exposure to atmospheric oxygen in thepresence of catalytic SiO₂.

Another method of making compounds of formula II is by adapting thefollowing synthesis of compound 38 of the form:

which is as follows:

where alpha tocotrienol quinone 28 is protected as itsdimethylhydroquinone 39 followed by conversion to tertiary chloride 40by treatment with dimethylchlorosliane, benzil and catalytic indiumchloride as described in Org. Syn. 2006, 83, 38-44. The methyl groupsare then removed by treatment with boron tribromide to givedihydroquinone 38, which can be oxidized to its corresponding quinone 41by treatment with CAN.

This method for synthesis of a compound of formula II can be adapted tothe following synthesis of compound 42 of the form:

which is as follows:

where alpha tocopherol quinone 43 is protected as itsdimethylhydroquinone 44 followed by conversion to tertiary chloride 45by treatment with dimethylchlorosliane, benzil and catalytic indiumchloride as described in Org. Syn. 2006, 83, 38-44. The methyl groupsare then removed by treatment with boron tribromide to givedihydroquinone 42, which can be oxidized to its corresponding quinone 46by treatment with CAN.Interconvertibility of Quinone, Dihydroquinone Forms

The quinone and dihydroquinone forms of the compounds disclosed hereinare readily interconverted with appropriate reagents. For example, thequinone form of a compound can be reduced to the dihydroquinone formwith reducing agents such as sodium dithionite. The hydroquinone formcan be oxidized to the quinone form with oxidizing agents such as cericammonium nitrate (CAN) or ferric chloride. The quinone and hydroquinoneforms are also readily converted electrochemically, as is well known inthe art. See, e.g., Section 33.4 of Streitweiser & Heathcock,Introduction to Organic Chemistry, New York: Macmillan, 1976.

When the compounds of the invention are drawn as the quinone orhydroquinone form, that specific form is intended. However, when thequinone form is drawn and followed by the phrase “reduced counterpartthereof” or “reduced form” or the like, the structure and the subsequentphrase are intended to embrace both the quinone and hydroquinone.Similarly, when the hydroquinone form is drawn and followed by thephrase “oxidized counterpart thereof” or “oxidized form thereof” or thelike, the structure and the subsequent phrase are intended to embraceboth the hydroquinone and quinone.

Diseases Amenable to Treatment or Suppression with Compounds and Methodsof the Invention

A variety of diseases are believed to be caused or aggravated bymitochondrial disorders and impaired energy processing, and can betreated or suppressed using the compounds and methods of the invention.Such diseases include, but are not limited to, inherited mitochondrialdiseases, such as Myoclonic Epilepsy with Ragged Red Fibers (MERRF),Mitochondrial Myopathy, Encephalopathy, Lactacidosis, Stroke (MELAS),Leber's Hereditary Optic Neuropathy (LHON, also referred to as Leber'sDisease, Leber's Optic Atrophy (LOA), or Leber's Optic Neuropathy(LON)), Leigh Disease or Leigh Syndrome, Kearns-Sayre Syndrome (KSS),Friedreich's Ataxia (FA), other myopathies (including cardiomyopathy andencephalomyopathy), and renal tubular acidosis; neurodegenerativediseases, such as Parkinson's disease, Alzheimer's disease, amyotrophiclateral sclerosis (ALS, also known as Lou Gehrig's disease), motorneuron diseases; other neurological diseases such as epilepsy; geneticdiseases such as Huntington's Disease (which is also a neurologicaldisease); mood disorders such as schizophrenia and bipolar disorder; andcertain age-associated diseases, particularly diseases for which CoQ10has been proposed for treatment, such as macular degeneration, diabetes,and cancer.

In Vitro Assessment of Efficacy of Compounds

The compounds of the invention can be tested in vitro for efficacy. Onesuch assay is ability of a compound to rescue FRDA fibroblasts stressedby addition of L-buthionine-(S,R)-sulfoximine (BSO), as described inJauslin et al., Hum. Mol. Genet. 11(24):3055 (2002), Jauslin et al.,FASEB J. 17:1972-4 (2003), and International Patent Application WO2004/003565. Human dermal fibroblasts from Friedreich's Ataxia patientshave been shown to be hypersensitive to inhibition of the de novosynthesis of glutathione (GSH) with L-buthionine-(S,R)-sulfoximine(BSO), a specific inhibitor of GSH synthetase (Jauslin et al., Hum. Mol.Genet. 11(24):3055 (2002)). This specific BSO-mediated cell death can beprevented by administration of antioxidants or molecules involved in theantioxidant pathway, such as α-tocopherol, short chain quinones,selenium, or small molecule glutathione peroxidase mimetics. However,antioxidants differ in their potency, i.e. the concentration at whichthey are able to rescue BSO-stressed FRDA fibroblasts. With this assay,EC₅₀ concentrations of the compounds of the invention can be determinedand compared to known reference antioxidants.

Clinical Assessment of Mitochondrial Dysfunction and Efficacy of Therapy

Several readily measurable clinical markers are used to assess themetabolic state of patients with mitochondrial disorders. These markerscan also be used as indicators of the efficacy of a given therapy, asthe level of a marker is moved from the pathological value to thehealthy value. These clinical markers include, but are not limited to,one or more of the previously discussed energy biomarkers, such aslactic acid (lactate) levels, either in whole blood, plasma,cerebrospinal fluid, or cerebral ventricular fluid; pyruvic acid(pyruvate) levels, either in whole blood, plasma, cerebrospinal fluid,or cerebral ventricular fluid; lactate/pyruvate ratios, either in wholeblood, plasma, cerebrospinal fluid, or cerebral ventricular fluid;phosphocreatine levels, NADH (NADH+H⁺) or NADPH (NADPH+H⁺) levels; NADor NADP levels; ATP levels; anaerobic threshold; reduced coenzyme Q(CoQ^(red)) levels; oxidized coenzyme Q (CoQ^(ox)) levels; totalcoenzyme Q (CoQ^(tot)) levels; oxidized cytochrome C levels; reducedcytochrome C levels; oxidized cytochrome C/reduced cytochrome C ratio;acetoacetate levels, β-hydroxy butyrate levels, acetoacetate/β-hydroxybutyrate ratio, 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels; levels ofreactive oxygen species; and levels of oxygen consumption (VO2), levelsof carbon dioxide output (VCO2), and respiratory quotient (VCO2/VO2).Several of these clinical markers are measured routinely in exercisephysiology laboratories, and provide convenient assessments of themetabolic state of a subject. In one embodiment of the invention, thelevel of one or more energy biomarkers in a patient suffering from amitochondrial disease, such as Friedreich's ataxia, Leber's hereditaryoptic neuropathy, MELAS, or KSS, is improved to within two standarddeviations of the average level in a healthy subject. In anotherembodiment of the invention, the level of one or more of these energybiomarkers in a patient suffering from a mitochondrial disease, such asFriedreich's ataxia, Leber's hereditary optic neuropathy, MELAS, or KSSis improved to within one standard deviation of the average level in ahealthy subject. Exercise intolerance can also be used as an indicatorof the efficacy of a given therapy, where an improvement in exercisetolerance (i.e., a decrease in exercise intolerance) indicates efficacyof a given therapy.

Several metabolic biomarkers have already been used to evaluate efficacyof CoQ10, and these metabolic biomarkers can be monitored as energybiomarkers for use in the methods of the current invention. Pyruvate, aproduct of the anaerobic metabolism of glucose, is removed by reductionto lactic acid in an anaerobic setting or by oxidative metabolism, whichis dependent on a functional mitochondrial respiratory chain.Dysfunction of the respiratory chain may lead to inadequate removal oflactate and pyruvate from the circulation and elevated lactate/pyruvateratios are observed in mitochondrial cytopathies (see Scriver C R, Themetabolic and molecular bases of inherited disease, 7th ed., New York:McGraw-Hill, Health Professions Division, 1995; and Munnich et al., J.Inherit. Metab. Dis. 15(4):448-55 (1992)). Blood lactate/pyruvate ratio(Chariot et al., Arch. Pathol. Lab. Med. 118(7):695-7 (1994)) is,therefore, widely used as a noninvasive test for detection ofmitochondrial cytopathies (see again Scriver C R, The metabolic andmolecular bases of inherited disease, 7th ed., New York: McGraw-Hill,Health Professions Division, 1995; and Munnich et al., J. Inherit.Metab. Dis. 15(4):448-55 (1992)) and toxic mitochondrial myopathies(Chariot et al., Arthritis Rheum. 37(4):583-6 (1994)). Changes in theredox state of liver mitochondria can be investigated by measuring thearterial ketone body ratio (acetoacetate/3-hydroxybutyrate: AKBR) (Uedaet al., J. Cardiol. 29(2):95-102 (1997)). Urinary excretion of8-hydroxy-2′-deoxyguanosine (8-OHdG) often has been used as a biomarkerto assess the extent of repair of ROS-induced DNA damage in bothclinical and occupational settings (Erhola et al., FEBS Lett.409(2):287-91 (1997); Honda et al., Leuk. Res. 24(6):461-8 (2000);Pilger et al., Free Radic. Res. 35(3):273-80 (2000); Kim et al. EnvironHealth Perspect 112(6):666-71 (2004)).

Magnetic resonance spectroscopy (MRS) has been useful in the diagnosesof mitochondrial cytopathy by demonstrating elevations in cerebrospinalfluid (CSF) and cortical white matter lactate using proton MRS (1H-MRS)(Kaufmann et al., Neurology 62(8):1297-302 (2004)). Phosphorous MRS(31P-MRS) has been used to demonstrate low levels of corticalphosphocreatine (PCr) (Matthews et al., Ann. Neurol. 29(4):435-8(1991)), and a delay in PCr recovery kinetics following exercise inskeletal muscle (Matthews et al., Ann. Neurol. 29(4):435-8 (1991);Barbiroli et al., J. Neurol. 242(7):472-7 (1995); Fabrizi et al., J.Neurol. Sci. 137(1):20-7 (1996)). A low skeletal muscle PCr has alsobeen confirmed in patients with mitochondrial cytopathy by directbiochemical measurements.

Exercise testing is particularly helpful as an evaluation and screeningtool in mitochondrial myopathies. One of the hallmark characteristics ofmitochondrial myopathies is a reduction in maximal whole body oxygenconsumption (VO2max) (Taivassalo et al., Brain 126(Pt 2):413-23 (2003)).Given that VO2max is determined by cardiac output (Qc) and peripheraloxygen extraction (arterial-venous total oxygen content) difference,some mitochondrial cytopathies affect cardiac function where deliverycan be altered; however, most mitochondrial myopathies show acharacteristic deficit in peripheral oxygen extraction (A-V O2difference) and an enhanced oxygen delivery (hyperkinetic circulation)(Taivassalo et al., Brain 126(Pt 2):413-23 (2003)). This can bedemonstrated by a lack of exercise induced deoxygenation of venous bloodwith direct AV balance measurements (Taivassalo et al., Ann. Neurol.51(1):38-44 (2002)) and non-invasively by near infrared spectroscopy(Lynch et al., Muscle Nerve 25(5):664-73 (2002); van Beekvelt et al.,Ann. Neurol. 46(4):667-70 (1999)).

Several of these energy biomarkers are discussed in more detail asfollows. It should be emphasized that, while certain energy biomarkersare discussed and enumerated herein, the invention is not limited tomodulation, normalization or enhancement of only these enumerated energybiomarkers.

Lactic Acid (Lactate) Levels:

Mitochondrial dysfunction typically results in abnormal levels of lacticacid, as pyruvate levels increase and pyruvate is converted to lactateto maintain capacity for glycolysis. Mitochondrial dysfunction can alsoresult in abnormal levels of NADH+H⁺, NADPH+H⁺, NAD, or NADP, as thereduced nicotinamide adenine dinucleotides are not efficiently processedby the respiratory chain. Lactate levels can be measured by takingsamples of appropriate bodily fluids such as whole blood, plasma, orcerebrospinal fluid. Using magnetic resonance, lactate levels can bemeasured in virtually any volume of the body desired, such as the brain.

Measurement of cerebral lactic acidosis using magnetic resonance inMELAS patients is described in Kaufmann et al., Neurology 62(8):1297(2004). Values of the levels of lactic acid in the lateral ventricles ofthe brain are presented for two mutations resulting in MELAS, A3243G andA8344G. Whole blood, plasma, and cerebrospinal fluid lactate levels canbe measured by commercially available equipment such as the YSI 2300STAT Plus Glucose & Lactate Analyzer (YSI Life Sciences, Ohio).

NAD, NADP, NADH and NADPH Levels:

Measurement of NAD, NADP, NADH (NADH+H⁺) or NADPH (NADPH+H⁺) can bemeasured by a variety of fluorescent, enzymatic, or electrochemicaltechniques, e.g., the electrochemical assay described in US2005/0067303.

Oxygen Consumption (vO₂ or VO2), Carbon Dioxide Output (vCO₂ or VCO2),and Respiratory Quotient (VCO2/VO2):

vO₂ is usually measured either while resting (resting vO₂) or at maximalexercise intensity (vO₂ max). Optimally, both values will be measured.However, for severely disabled patients, measurement of vO₂ max may beimpractical. Measurement of both forms of vO₂ is readily accomplishedusing standard equipment from a variety of vendors, e.g. Korr MedicalTechnologies, Inc. (Salt Lake City, Utah). VCO2 can also be readilymeasured, and the ratio of VCO2 to VO2 under the same conditions(VCO2/VO2, either resting or at maximal exercise intensity) provides therespiratory quotient (RQ).

Oxidized Cytochrome C, Reduced Cytochrome C, and Ratio of OxidizedCytochrome C to Reduced Cytochrome C:

Cytochrome C parameters, such as oxidized cytochrome C levels (CytC_(ox)), reduced cytochrome C levels (Cyt C_(red)), and the ratio ofoxidized cytochrome C/reduced cytochrome C ratio (Cyt C_(ox))/(CytC_(red)), can be measured by in vivo near infrared spectroscopy. See,e.g., Rolfe, P., “In vivo near-infrared spectroscopy,” Annu. Rev.Biomed. Eng. 2:715-54 (2000) and Strangman et al., “Non-invasiveneuroimaging using near-infrared light” Biol. Psychiatry 52:679-93(2002).

Exercise Tolerance/Exercise Intolerance:

Exercise intolerance is defined as “the reduced ability to performactivities that involve dynamic movement of large skeletal musclesbecause of symptoms of dyspnea or fatigue” (Piña et al., Circulation107:1210 (2003)). Exercise intolerance is often accompanied bymyoglobinuria, due to breakdown of muscle tissue and subsequentexcretion of muscle myoglobin in the urine. Various measures of exerciseintolerance can be used, such as time spent walking or running on atreadmill before exhaustion, time spent on an exercise bicycle(stationary bicycle) before exhaustion, and the like. Treatment with thecompounds or methods of the invention can result in about a 10% orgreater improvement in exercise tolerance (for example, about a 10% orgreater increase in time to exhaustion, e.g. from 10 minutes to 11minutes), about a 20% or greater improvement in exercise tolerance,about a 30% or greater improvement in exercise tolerance, about a 40% orgreater improvement in exercise tolerance, about a 50% or greaterimprovement in exercise tolerance, about a 75% or greater improvement inexercise tolerance, or about a 100% or greater improvement in exercisetolerance. While exercise tolerance is not, strictly speaking, an energybiomarker, for the purposes of the invention, modulation, normalization,or enhancement of energy biomarkers includes modulation, normalization,or enhancement of exercise tolerance.

Similarly, tests for normal and abnormal values of pyruvic acid(pyruvate) levels, lactate/pyruvate ratio, ATP levels, anaerobicthreshold, reduced coenzyme Q (CoQ^(red)) levels, oxidized coenzyme Q(CoQ^(ox)) levels, total coenzyme Q (CoQ^(tot)) levels, oxidizedcytochrome C levels, reduced cytochrome C levels, oxidized cytochromeC/reduced cytochrome C ratio, acetoacetate levels, β-hydroxy butyratelevels, acetoacetate/β-hydroxy butyrate ratio,8-hydroxy-2′-deoxyguanosine (8-OHdG) levels, and levels of reactiveoxygen species are known in the art and can be used to evaluate efficacyof the compounds and methods of the invention. (For the purposes of theinvention, modulation, normalization, or enhancement of energybiomarkers includes modulation, normalization, or enhancement ofanaerobic threshold.)

Table 1, following, illustrates the effect that various dysfunctions canhave on biochemistry and energy biomarkers. It also indicates thephysical effect (such as a disease symptom or other effect of thedysfunction) typically associated with a given dysfunction. It should benoted that any of the energy biomarkers listed in the table, in additionto energy biomarkers enumerated elsewhere, can also be modulated,enhanced, or normalized by the compounds and methods of the invention.RQ=respiratory quotient; BMR=basal metabolic rate; HR (CO)=heart rate(cardiac output); T=body temperature (preferably measured as coretemperature); AT=anaerobic threshold; pH=blood pH (venous and/orarterial).

TABLE 1 Site of Measurable Energy Dysfunction Biochemical EventBiomarker Physical Effect Respiratory ↑ NADH Δ lactate, Metabolic ChainΔ lactate:pyruvate ratio; dyscrasia & and fatigue Δacetoacetate:β-hydroxy butyrate ratio Respiratory ↓ H⁺ gradient Δ ATPOrgan dependent Chain dysfunction Respiratory ↓ Electron flux Δ VO₂, RQ,BMR, ΔT, Metabolic Chain AT, pH dyscrasia & fatigue Mitochondria & ↓ATP, ↓ VO₂ Δ Work, ΔHR (CO) Exercise cytosol intolerance Mitochondria &↓ ATP Δ PCr Exercise cytosol intolerance Respiratory ↓ Cyt C_(Ox/Red) Δλ~700-900 nM (Near Exercise Chain Infrared Spectroscopy) intoleranceIntermediary ↓ Catabolism Δ C¹⁴-Labeled substrates Metabolic metabolismdyscrasia & fatigue Respiratory ↓ Electron flux Δ Mixed Venous VO₂Metabolic Chain dyscrasia & fatigue Mitochondria & ↑ Oxidative stress ΔTocopherol & Uncertain cytosol Tocotrienols, CoQ10, docosahexanoic acidMitochondria & ↑ Oxidative stress Δ Glutathione_(red) Uncertain cytosolMitochondria & Nucleic acid Δ8-hydroxy 2-deoxy Uncertain cytosoloxidation guanosine Mitochondria & Lipid oxidation ΔIsoprostane(s),Uncertain cytosol eicasanoids Cell membranes Lipid oxidation ΔEthane(breath) Uncertain Cell membranes Lipid oxidation ΔMalondialdehydeUncertain

Treatment of a subject afflicted by a mitochondrial disease inaccordance with the methods of the invention may result in theinducement of a reduction or alleviation of symptoms in the subject,e.g., to halt the further progression of the disorder.

Partial or complete suppression of the mitochondrial disease can resultin a lessening of the severity of one or more of the symptoms that thesubject would otherwise experience. For example, partial suppression ofMELAS could result in reduction in the number of stroke-like or seizureepisodes suffered.

Any one, or any combination of, the energy biomarkers described hereinprovide conveniently measurable benchmarks by which to gauge theeffectiveness of treatment or suppressive therapy. Additionally, otherenergy biomarkers are known to those skilled in the art and can bemonitored to evaluate the efficacy of treatment or suppressive therapy.

Use of Compounds for Modulation of Energy Biomarkers

In addition to monitoring energy biomarkers to assess the status oftreatment or suppression of mitochondrial diseases, the compounds of theinvention can be used in subjects or patients to modulate one or moreenergy biomarkers. Modulation of energy biomarkers can be done tonormalize energy biomarkers in a subject, or to enhance energybiomarkers in a subject.

Normalization of one or more energy biomarkers is defined as eitherrestoring the level of one or more such energy biomarkers to normal ornear-normal levels in a subject whose levels of one or more energybiomarkers show pathological differences from normal levels (i.e.,levels in a healthy subject), or to change the levels of one or moreenergy biomarkers to alleviate pathological symptoms in a subject.Depending on the nature of the energy biomarker, such levels may showmeasured values either above or below a normal value. For example, apathological lactate level is typically higher than the lactate level ina normal (i.e., healthy) person, and a decrease in the level may bedesirable. A pathological ATP level is typically lower than the ATPlevel in a normal (i.e., healthy) person, and an increase in the levelof ATP may be desirable. Accordingly, normalization of energy biomarkerscan involve restoring the level of energy biomarkers to within about atleast two standard deviations of normal in a subject, more preferably towithin about at least one standard deviation of normal in a subject, towithin about at least one-half standard deviation of normal, or towithin about at least one-quarter standard deviation of normal.

When an increase in an energy biomarker level is desired to normalizethe one or more such energy biomarker, the level of the energy biomarkercan be increased to within about at least two standard deviations ofnormal in a subject, more preferably increased to within about at leastone standard deviation of normal in a subject, increased to within aboutat least one-half standard deviation of normal, or increased to withinabout at least one-quarter standard deviation of normal, byadministration of one or more compounds according to the invention.Alternatively, the level of one or more of the energy biomarkers can beincreased by about at least 10% above the subject's level of therespective one or more energy biomarkers before administration; by aboutat least 20% above the subject's level of the respective one or moreenergy biomarkers before administration, by about at least 30% above thesubject's level of the respective one or more energy biomarkers beforeadministration, by about at least 40% above the subject's level of therespective one or more energy biomarkers before administration, by aboutat least 50% above the subject's level of the respective one or moreenergy biomarkers before administration, by about at least 75% above thesubject's level of the respective one or more energy biomarkers beforeadministration, or by about at least 100% above the subject's level ofthe respective one or more energy biomarkers before administration.

When a decrease in a level of one or more energy biomarkers is desiredto normalize the one or more energy biomarkers, the level of the one ormore energy biomarkers can be decreased to a level within about at leasttwo standard deviations of normal in a subject, more preferablydecreased to within about at least one standard deviation of normal in asubject, decreased to within about at least one-half standard deviationof normal, or decreased to within about at least one-quarter standarddeviation of normal, by administration of one or more compoundsaccording to the invention. Alternatively, the level of the one or moreenergy biomarkers can be decreased by about at least 10% below thesubject's level of the respective one or more energy biomarkers beforeadministration, by about at least 20% below the subject's level of therespective one or more energy biomarkers before administration, by aboutat least 30% below the subject's level of the respective one or moreenergy biomarkers before administration, by about at least 40% below thesubject's level of the respective one or more energy biomarkers beforeadministration, by about at least 50% below the subject's level of therespective one or more energy biomarkers before administration, by aboutat least 75% below the subject's level of the respective one or moreenergy biomarkers before administration, or by about at least 90% belowthe subject's level of the respective one or more energy biomarkersbefore administration.

Enhancement of the level of one or more energy biomarkers is defined aschanging the extant levels of one or more energy biomarkers in a subjectto a level which provides beneficial or desired effects for the subject.For example, a person undergoing strenuous effort or prolonged vigorousphysical activity, such as mountain climbing, could benefit fromincreased ATP levels or decreased lactate levels. As described above,normalization of energy biomarkers may not achieve the optimum state fora subject with a mitochondrial disease, and such subjects can alsobenefit from enhancement of energy biomarkers. Examples of subjects whocould benefit from enhanced levels of one or more energy biomarkersinclude, but are not limited to, subjects undergoing strenuous orprolonged physical activity, subjects with chronic energy problems, orsubjects with chronic respiratory problems. Such subjects include, butare not limited to, pregnant females, particularly pregnant females inlabor; neonates, particularly premature neonates; subjects exposed toextreme environments, such as hot environments (temperatures routinelyexceeding about 85-86 degrees Fahrenheit or about 30 degrees Celsius forabout 4 hours daily or more), cold environments (temperatures routinelybelow about 32 degrees Fahrenheit or about 0 degrees Celsius for about 4hours daily or more), or environments with lower-than-average oxygencontent, higher-than-average carbon dioxide content, orhigher-than-average levels of air pollution (airline travelers, flightattendants, subjects at elevated altitudes, subjects living in citieswith lower-than-average air quality, subjects working in enclosedenvironments where air quality is degraded); subjects with lung diseasesor lower-than-average lung capacity, such as tubercular patients, lungcancer patients, emphysema patients, and cystic fibrosis patients;subjects recovering from surgery or illness; elderly subjects, includingelderly subjects experiencing decreased energy; subjects suffering fromchronic fatigue, including chronic fatigue syndrome; subjects undergoingacute trauma; subjects in shock; subjects requiring acute oxygenadministration; subjects requiring chronic oxygen administration; orother subjects with acute, chronic, or ongoing energy demands who canbenefit from enhancement of energy biomarkers.

Accordingly, when an increase in a level of one or more energybiomarkers is beneficial to a subject, enhancement of the one or moreenergy biomarkers can involve increasing the level of the respectiveenergy biomarker or energy biomarkers to about at least one-quarterstandard deviation above normal, about at least one-half standarddeviation above normal, about at least one standard deviation abovenormal, or about at least two standard deviations above normal.Alternatively, the level of the one or more energy biomarkers can beincreased by about at least 10% above the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 20% above the subject's level of the respective one or more energybiomarkers before enhancement, by about at least 30% above the subject'slevel of the respective one or more energy biomarkers beforeenhancement, by about at least 40% above the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 50% above the subject's level of the respective one or more energybiomarkers before enhancement, by about at least 75% above the subject'slevel of the respective one or more energy biomarkers beforeenhancement, or by about at least 100% above the subject's level of therespective one or more energy biomarkers before enhancement.

When a decrease in a level of one or more energy biomarkers is desiredto enhance one or more energy biomarkers, the level of the one or moreenergy biomarkers can be decreased by an amount of about at leastone-quarter standard deviation of normal in a subject, decreased byabout at least one-half standard deviation of normal in a subject,decreased by about at least one standard deviation of normal in asubject, or decreased by about at least two standard deviations ofnormal in a subject. Alternatively, the level of the one or more energybiomarkers can be decreased by about at least 10% below the subject'slevel of the respective one or more energy biomarkers beforeenhancement, by about at least 20% below the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 30% below the subject's level of the respective one or more energybiomarkers before enhancement, by about at least 40% below the subject'slevel of the respective one or more energy biomarkers beforeenhancement, by about at least 50% below the subject's level of therespective one or more energy biomarkers before enhancement, by about atleast 75% below the subject's level of the respective one or more energybiomarkers before enhancement, or by about at least 90% below thesubject's level of the respective one or more energy biomarkers beforeenhancement.

Use of Compounds in Research Applications, Experimental Systems, andAssays

The compounds of the invention can also be used in researchapplications, such as in in vitro, in vivo, or ex vivo experiments inorder to modulate one or more energy biomarkers in an experimentalsystem. Such experimental systems can be cell samples, tissue samples,cell components or mixtures of cell components, partial organs, wholeorgans, or organisms. Such research applications can include, but arenot limited to, use as assay reagents, elucidation of biochemicalpathways, or evaluation of the effects of other agents on the metabolicstate of the experimental system in the presence/absence of one or morecompounds of the invention.

Additionally, the compounds of the invention can be used in biochemicaltests or assays. Such tests can include incubation of one or morecompounds of the invention with a tissue or cell sample from a subjectto evaluate a subject's potential response (or the response of aspecific subset of subjects) to administration of said one or morecompounds, or to determine which compound of the invention produces theoptimum effect in a specific subject or subset of subjects. One suchtest or assay would involve 1) obtaining a cell sample or tissue samplefrom a subject or set of subjects in which modulation of one or moreenergy biomarkers can be assayed; 2) administering one or more compoundsof the invention to the cell sample(s) or tissue sample(s); and 3)determining the amount of modulation of the one or more energybiomarkers after administration of the one or more compounds, comparedto the status of the energy biomarker prior to administration of the oneor more compounds. Another such test or assay would involve 1) obtaininga cell sample or tissue sample from a subject or set of subjects inwhich modulation of one or more energy biomarkers can be assayed; 2)administering at least two compounds of the invention to the cellsample(s) or tissue sample(s); 3) determining the amount of modulationof the one or more energy biomarkers after administration of the atleast two compounds, compared to the status of the energy biomarkerprior to administration of the at least two compounds, and 4) selectinga compound for use in treatment, suppression, or modulation based on theamount of modulation determined in step 3).

Pharmaceutical Formulations

The compounds described herein can be formulated as pharmaceuticalcompositions by formulation with additives such as pharmaceuticallyacceptable excipients, pharmaceutically acceptable carriers, andpharmaceutically acceptable vehicles. Suitable pharmaceuticallyacceptable excipients, carriers and vehicles include processing agentsand drug delivery modifiers and enhancers, such as, for example, calciumphosphate, magnesium stearate, talc, monosaccharides, disaccharides,starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-β-cyclodextrin,polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and thelike, as well as combinations of any two or more thereof. Other suitablepharmaceutically acceptable excipients are described in “Remington'sPharmaceutical Sciences,” Mack Pub. Co., New Jersey (1991), and“Remington: The Science and Practice of Pharmacy,” Lippincott Williams &Wilkins, Philadelphia, 20th edition (2003) and 21st edition (2005),incorporated herein by reference.

A pharmaceutical composition can comprise a unit dose formulation, wherethe unit dose is a dose sufficient to have a therapeutic or suppressiveeffect or an amount effective to modulate, normalize, or enhance anenergy biomarker. The unit dose may be sufficient as a single dose tohave a therapeutic or suppressive effect or an amount effective tomodulate, normalize, or enhance an energy biomarker. Alternatively, theunit dose may be a dose administered periodically in a course oftreatment or suppression of a disorder, or to modulate, normalize, orenhance an energy biomarker.

Pharmaceutical compositions containing the compounds of the inventionmay be in any form suitable for the intended method of administration,including, for example, a solution, a suspension, or an emulsion. Liquidcarriers are typically used in preparing solutions, suspensions, andemulsions. Liquid carriers contemplated for use in the practice of thepresent invention include, for example, water, saline, pharmaceuticallyacceptable organic solvent(s), pharmaceutically acceptable oils or fats,and the like, as well as mixtures of two or more thereof. The liquidcarrier may contain other suitable pharmaceutically acceptable additivessuch as solubilizers, emulsifiers, nutrients, buffers, preservatives,suspending agents, thickening agents, viscosity regulators, stabilizers,and the like. Suitable organic solvents include, for example, monohydricalcohols, such as ethanol, and polyhydric alcohols, such as glycols.Suitable oils include, for example, soybean oil, coconut oil, olive oil,safflower oil, cottonseed oil, and the like. For parenteraladministration, the carrier can also be an oily ester such as ethyloleate, isopropyl myristate, and the like. Compositions of the presentinvention may also be in the form of microparticles, microcapsules,liposomal encapsulates, and the like, as well as combinations of any twoor more thereof.

Time-release or controlled release delivery systems may be used, such asa diffusion controlled matrix system or an erodible system, as describedfor example in: Lee, “Diffusion-Controlled Matrix Systems”, pp. 155-198and Ron and Langer, “Erodible Systems”, pp. 199-224, in “Treatise onControlled Drug Delivery”, A. Kydonieus Ed., Marcel Dekker, Inc., NewYork 1992. The matrix may be, for example, a biodegradable material thatcan degrade spontaneously in situ and in vivo for, example, byhydrolysis or enzymatic cleavage, e.g., by proteases. The deliverysystem may be, for example, a naturally occurring or synthetic polymeror copolymer, for example in the form of a hydrogel. Exemplary polymerswith cleavable linkages include polyesters, polyorthoesters,polyanhydrides, polysaccharides, poly(phosphoesters), polyamides,polyurethanes, poly(imidocarbonates) and poly(phosphazenes).

The compounds of the invention may be administered enterally, orally,parenterally, sublingually, by inhalation (e.g. as mists or sprays),rectally, or topically in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles as desired. For example, suitable modes of administrationinclude oral, subcutaneous, transdermal, transmucosal, iontophoretic,intravenous, intraarterial, intramuscular, intraperitoneal, intranasal(e.g. via nasal mucosa), subdural, rectal, gastrointestinal, and thelike, and directly to a specific or affected organ or tissue. Fordelivery to the central nervous system, spinal and epiduraladministration, or administration to cerebral ventricles, can be used.Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. The compounds are mixed with pharmaceutically acceptablecarriers, adjuvants, and vehicles appropriate for the desired route ofadministration. Oral administration is a preferred route ofadministration, and formulations suitable for oral administration arepreferred formulations. The compounds described for use herein can beadministered in solid form, in liquid form, in aerosol form, or in theform of tablets, pills, powder mixtures, capsules, granules,injectables, creams, solutions, suppositories, enemas, colonicirrigations, emulsions, dispersions, food premixes, and in othersuitable forms. The compounds can also be administered in liposomeformulations. The compounds can also be administered as prodrugs, wherethe prodrug undergoes transformation in the treated subject to a formwhich is therapeutically effective. Additional methods of administrationare known in the art.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in propylene glycol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols that are solid at room temperature butliquid at the rectal temperature and will therefore melt in the rectumand release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also compriseadditional substances other than inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multilamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic. Methodsto form liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., p.33 et seq (1976).

The invention also provides articles of manufacture and kits containingmaterials useful for treating or suppressing mitochondrial diseases. Thearticle of manufacture comprises a container with a label. Suitablecontainers include, for example, bottles, vials, and test tubes. Thecontainers may be formed from a variety of materials such as glass orplastic. The container holds a composition having an active agent whichis effective for treating or suppressing mitochondrial diseases. Theactive agent in the composition is one or more of the compounds of theinvention. The label on the container indicates that the composition isused for treating or suppressing mitochondrial diseases, and may alsoindicate directions for either in vivo or in vitro use, such as thosedescribed above.

The invention also provides kits comprising any one or more of thecompounds of the invention. In some embodiments, the kit of theinvention comprises the container described above. In other embodiments,the kit of the invention comprises the container described above and asecond container comprising a buffer. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, syringes, and package insertswith instructions for performing any methods described herein.

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with amitochondrial disorder, or to suppress a mitochondrial disorder in anindividual.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost to which the active ingredient is administered and the particularmode of administration. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, body area, body mass index (BMI),general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the type,progression, and severity of the particular disease undergoing therapy.The pharmaceutical unit dosage chosen is usually fabricated andadministered to provide a defined final concentration of drug in theblood, tissues, organs, or other targeted region of the body. Thetherapeutically effective amount or effective amount for a givensituation can be readily determined by routine experimentation and iswithin the skill and judgment of the ordinary clinician.

Examples of dosages which can be used are an effective amount within thedosage range of about 0.1 μg/kg to about 300 mg/kg, or within about 1.0μg/kg to about 40 mg/kg body weight, or within about 1.0 μg/kg to about20 mg/kg body weight, or within about 1.0 μg/kg to about 10 mg/kg bodyweight, or within about 10.0 μg/kg to about 10 mg/kg body weight, orwithin about 100 μg/kg to about 10 mg/kg body weight, or within about1.0 mg/kg to about 10 mg/kg body weight, or within about 10 mg/kg toabout 100 mg/kg body weight, or within about 50 mg/kg to about 150 mg/kgbody weight, or within about 100 mg/kg to about 200 mg/kg body weight,or within about 150 mg/kg to about 250 mg/kg body weight, or withinabout 200 mg/kg to about 300 mg/kg body weight, or within about 250mg/kg to about 300 mg/kg body weight. Other dosages which can be usedare about 0.01 mg/kg body weight, about 0.1 mg/kg body weight, about 1mg/kg body weight, about 10 mg/kg body weight, about 20 mg/kg bodyweight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50mg/kg body weight, about 75 mg/kg body weight, about 100 mg/kg bodyweight, about 125 mg/kg body weight, about 150 mg/kg body weight, about175 mg/kg body weight, about 200 mg/kg body weight, about 225 mg/kg bodyweight, about 250 mg/kg body weight, about 275 mg/kg body weight, orabout 300 mg/kg body weight. Compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided dosage of two, three or four times daily.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents used in the treatment or suppression ofdisorders. Representative agents useful in combination with thecompounds of the invention for the treatment or suppression ofmitochondrial diseases include, but are not limited to, Coenzyme Q,vitamin E, idebenone, MitoQ, vitamins, and antioxidant compounds.

When additional active agents are used in combination with the compoundsof the present invention, the additional active agents may generally beemployed in therapeutic amounts as indicated in the Physicians' DeskReference (PDR) 53rd Edition (1999), which is incorporated herein byreference, or such therapeutically useful amounts as would be known toone of ordinary skill in the art.

The compounds of the invention and the other therapeutically activeagents can be administered at the recommended maximum clinical dosage orat lower doses. Dosage levels of the active compounds in thecompositions of the invention may be varied so as to obtain a desiredtherapeutic response depending on the route of administration, severityof the disease and the response of the patient. When administered incombination with other therapeutic agents, the therapeutic agents can beformulated as separate compositions that are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

The invention will be further understood by the following nonlimitingexamples.

EXAMPLES Example 1 Synthesis of Compounds2,3-Dimethyl-5,6-bis-(3-methyl-butyl)-[1,4]benzoquinone

A solution of FeCl₃.6H₂O (81.0 g, 300 mmol) in water (100 mL) was addedto a solution of 2,3-dimethyl-benzene-1,4-diol (13.8 g, 100 mmol) inMTBE (150 ml) at ambient temperature. Aqueous sodium hydroxide solution(2.5M, 60 mL, 150 mmol) was added to the vigorously stirring mixture andthe reaction heated to 50° C. for 5 hrs. MTBE (150 mL) and water (150mL) were added and the aqueous layer further extracted with MTBE (2×100mL). The combined organics were washed with brine (100 mL), dried(Na₂SO₄), and concentrated to give the intermediate2,3-dimethyl-[1,4]benzoquinone as an orange-yellow solid (12.0 g, 88%),which was used in the next step without further purification.

A solution of silver(I) nitrate (3.40 g, 20 mmol) in water (50 mL) wasadded to a mixture of 2,3-dimethyl-[1,4]benzoquinone (1.36 g, 10 mmol)and 4-methylpentanoic acid (1.26 mL, 1.16 g, 20 mmol) in acetonitrile(50 mL) at ambient temperature. The mixture was stirred vigorously,heated to 75-80° C., and a solution of ammonium persulfate (4.56 g, 20mmol) in water (30 mL) added dropwise via syringe-pump over 4 hrs. Aftera total 20 hrs the majority of the acetonitrile was removed using arotorevaporator, the residue partitioned between MTBE (100 mL) and water(100 mL), and the aqueous layer further extracted with MTBE (50 mL). Thecombined organics were washed with 1:1 saturated brine-water (50 mL) andthen concentrated. The orange-red residue was purified by columnchromatography on silica-gel using a gradient elution of 1 to 2.5%EtOAc-hexanes to give the2,3-Dimethyl-5,6-bis-(3-methyl-butyl)-[1,4]benzoquinone as a yellow oil(200 mg, 7%). ¹H-NMR (CDCl₃, 400 MHz, δ ppm): 2.42-2.38 (4H, m), 1.99(6H, s), 1.62 (2H, nonet, J=7 Hz), 1.28-1.22 (4H, m), 0.93 (12H, d, J=7Hz). ¹³C-NMR (CDCl₃, 100 MHz, δ ppm): 187.60, 144.35, 140.39, 38.66,28.71, 24.55, 22.35, 12.28.

2-(3-Hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-but-2-enyl)-[1,4]benzoquinone

To a stirring solution of 113 mg2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol (prepared inthe method of Walkinshaw, et al., US 2005/0065099 A1, Mar. 24, 2005) in3.75 mL acetonitrile-water (5:1) at 5° C. was added a yellow solution ofcerium(IV) ammonium nitrate (475 mg) in acetonitrile-water (1:4, 2.75mL) over a period of 5 minutes. The reaction mixture was allowed to stirfor an additional 5 minutes, after which it was poured into a separatoryfunnel containing dichloromethane (30 mL) and water (30 mL). The aqueouslayer was removed and the remaining organics were washed once with 1.0 Msodium chloride solution (30 mL). The organics were subsequently driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo.Silica gel chromatography (15% ethyl acetate-85% hexanes) provided 58 mgof2-(3-hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-but-2-enyl)-[1,4]benzoquinone.¹H NMR (CDCl₃, 400 MHz) 4.92 (t, 1H), 3.18 (d, 2H), 2.54 (t, 2H), 1.99(s, 6H), 1.74 (s, 3H), 1.66 (s, 3H), 1.52 (m, 2H), 1.26 (s, 6H).

2-(3-Hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-butyl)-[1,4]benzoquinone

To a solution of2,2,7,8-tetramethyl-5-(3-methyl-but-2-enyl)-chroman-6-ol (68 mg) inethyl acetate (2.4 mL) was added Pd/C (26 mg, 5% w/w). The resultingsuspension was flushed with hydrogen gas, the container sealed, and thecontents stirred under 1 atm of hydrogen gas for 30 min. The mixture wasthen filtered and concentrated in vacuo. The resulting residue wasdissolved in acetonitrile-water (5:1, 2.6 mL) and the solution cooled to5° C. in an ice-water bath. Into the reaction mixture was added asolution of cerium(IV) ammonium nitrate (287 mg) in acetonitrile-water(1:4, 1.6 mL) over a period of 5 minutes. The reaction mixture wasallowed to stir for an additional 5 minutes, after which it was pouredinto a separatory funnel containing dichloromethane (30 mL) and water(30 mL). The aqueous layer was removed and the remaining organics werewashed once with 1.0 M sodium chloride solution (30 mL). The organicswere subsequently dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. Silica gel chromatography (18% ethyl acetate-82%hexanes) provided 29 mg of2-(3-hydroxy-3-methyl-butyl)-5,6-dimethyl-3-(3-methyl-butyl)-[1,4]benzoquinone.¹H NMR (CDCl₃, 400 MHz) 2.53 (m, 2H), 2.43 (m, 2H), 1.99 (s, 3H), 1.62(m, 1H), 1.53 (m, 2H), 1.24 (m, 8H), 0.94 (s, 3H), 0.92 (s, 3H).

(E)-1-(7-chloro-3-methylhept-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene

Zirconocene dichloride (1.66 g, 5.6 mmol) was treated withdichloroethane (22 mL) and trimethylaluminum solution (23 mmol, 2.0 M inheptane) was added. The clear yellow solution was stirred for 0.75 h andcooled to 0° C. 5-chloro-1-pentyne was added neat over 1 h at 0° C. andstirred 10 h at room temperature. The clear brown solution wasconcentrated in vacuo and triturated with anhydrous hexanes (3×5 mL),the solvent being removed after each iteration via vacuum. Hexanes (10mL) was then added and the solution cannulated away from the solids. Thesolids were rinsed with hexanes (5 mL) and the combined hexane solutionsdiluted with THF (80 mL). A prepared solution of1-(chloromethyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (4.009 g, 17.5mmol) in THF (10 mL) was added to the vinyl alane via cannula and thecombined solution cooled to 10° C. The catalyst was prepared by treatingbis-(triphenylphosphine)nickel dichloride (579 mg, 0.87 mmol) in THF (5mL) with n-BuLi (1.6 M in hexanes, 1.75 mmol). The blood-red clearcatalyst solution was then added via cannula to the 10° C. vinyl alanesolution and let warm to room temperature over 7 h. The reaction wascooled to 0° C. and quenched by slow addition of 2.5 M HCl (100 mL) over0.5 h followed by hexanes (100 mL) and separation. The aqueous layer wasextracted 2×100 mL hexanes, 1×50 mL 50% EtOAc/hexanes and the combinedorganics washed once with brine (100 mL) and dried over anhydrous Na₂SO₄and concentrated to a brown oil. Multiple flash chromatography yielded5.2 g of(E)-1-(7-chloro-3-methylhept-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzeneas a clear oil (94.6%). ¹H NMR (400 MHz, CDCl₃) d 5.05 (t, J=6.4 Hz,1H), 3.63 (S, 6H), 3.49 (t, J=6.4 Hz, 2H), 3.35 (d, J=8.4 Hz, 1H), 2.16(s, 9H), 1.98 (t, J=7.6 Hz, 2H), 1.76 (s, 3H), 1.70 (m, 2H), 1.52 (m,2H). ¹³C NMR (100 MHz, CDCl₃) d 153.0, 152.7, 134.4, 131.4, 128.3,127.9, 127.6, 123.8, 60.9, 60.1, 45.0, 38.8, 32.2, 26.1, 25.1, 16.1,12.8, 12.7, 12.2.

(E)-2-(7-chloro-3-methylhept-2-enyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione

CAN (709 mg, 1.29 mmol) was dissolved into AcCN (7 mL) and water (3 mL)then cooled to 0° C. In a separate flask,(E)-1-(7-Chloro-3-methylhept-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene(175 mg, 0.53 mmol) was dissolved into AcCN (2 mL) and 1 drop of H₂O andtransferred to the stirring CAN solution. Stirring was maintained for 1h, after which time an additional charge of CAN (350 mg) was added andlet stir for 1 h. Water (10 mL) and EtOAc (10 mL) were added, the layersseparated and the combined organics washed H₂O (2×5 mL). The combinedaqueous phases were back extracted using EtOAc (2×5 mL) and the combinedorganics washed with brine (2×5 mL), dried over anhydrous Na₂SO₄ andconcentrated to a yellow oil. Flash chromatography (SiO₂) yielded 29.7mg of(E)-2-(7-chloro-3-methylhept-2-enyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dioneas a yellow oil (18.7%). ¹H NMR (400 MHz, CDCl₃) δ4.95 (t, J=6.8 Hz,1H), 3.50 (t, J=6.8 Hz, 2H), 3.19 (d, J=6.8 Hz, 2H), 2.00 (m, 11H), 1.71(m, 5H), 1.51 (m, J=7.2 Hz, 2H).

¹³C NMR (100 MHz, δ) 187.9, 187.0, 143.0, 140.4, 140.3, 136.5, 120.0,44.9, 38.8, 32.1, 25.6, 24.9, 16.1, 12.3, 12.2.

(E)-1-(6-chloro-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene

Zirconocene dichloride (982 mg, 3.36 mmol) was treated withtrimethylaluminum (13.1 mL, 2.0 M in heptane) and dichloroethane (13mL). The bright yellow solution was cooled to 0° C. and5-chloro-1-pentyne added over 5 minutes. The reaction was held at 0° C.for 0.25 h and warmed to room temperature. After 5.5 h the dark yellowsolution was reduced in vacuo to ca. 70% of its original volume andtriturated with hexanes (2×10 mL). A final portion of hexanes (10 mL)was added and cannulated away from the precipitated salts withadditional hexane wash (2×2 mL) to ensure complete transfer. The vinylalane which was subsequently diluted with THF (40 mL) and treated with1-(chloromethyl)-2,5-dimethoxy-3,4,6-trimethylbenzene (1.35 g) in THF(15 mL) via cannula. A separate flask containingbis-(triphenylphosphine)nickel dichloride (967 mg, 1.47 mmol) in THF (5mL) was treated with n-buLi (260 mL, 1.6 M in heptane, 0.416 mmol) togive a dark red, clear solution which was added to the vinyl alanesolution. The reaction was placed in a 15° C. water bath to control anexotherm and let stir overnight at room temperature. The reaction wasquenched by treatment with citric acid (11 g) in H₂O (50 mL) via slowaddition, followed by addition of hexanes (50 mL) and H₂O (50 mL) withstirring for an additional 20 minutes. The layers were separated and theaqueous phase extracted using hexanes (3×50 mL) then MTBE (2×50 mL). Thecombined organics were washed with brine (2×20 mL), dried over anhydrousNa₂SO₄ and concentrated to a brown oil. Flash chromatography yielded2.011 g (74.0%) of(E)-1-(6-chloro-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzeneas a clear oil.

¹H NMR (400 MHz, CDCl₃) d 5.11 (t, J=7.2 Hz, 1H), 3.65 (s, 6H), 3.48 (t,J=6.8 Hz, 2H), 3.76 (d, J=6.4 Hz, 2H), 2.18 (s, 9H), 2.10 (t, J=7.2 Hz,2H) 1.84 (quintet, J=7.2 Hz, 2H), 1.78 (s, 3H). ¹³C NMR (100 MHz, CDCl₃)d 153.0, 152.6, 133.4, 131.3, 128.4, 127.9, 127.6, 124.5, 60.9, 60.1,44.6, 36.6, 30.8, 26.1, 16.2, 12.8, 12.7, 12.2.

1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene

(E)-1-(6-chloro-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene(725.8 mg, 2.334 mmol) and NaI (3.09 g, 20.61 mmol) were dissolved intoacetone (10 mL) and heated to reflux for 18 h. The reaction mixture wascooled to room temperature and the cloudy solution added to H₂O (50 mL)and of a 50% EtOAc/hexanes solution (50 mL), the layers separated andthe aqueous phase extracted with hexanes (3×25 mL), then MTBE (2×25 mL).The organics were combined and washed with saturated NaCl solution (2×25mL) and dried over anhydrous Na₂SO₄. Concentration yielded 930.0 mg(99.0%) of1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzeneas a pale yellow oil. ¹H NMR (400 MHz, CDCl₃) d 5.12 (t, J=6.4 Hz, 1H),3.65 (s, 6H), 3.36 (d, J=6.0 Hz, 2H), 3.12 (t, J=7.2 Hz, 2H), 2.18 (S9H), 2.07 (t, J=7.2 Hz, 2H), 1.91 (t, J=7.2 HZ, 2H), 1.77 (s, 3H), ¹³CNMR (100 MHz, CDCl₃) d 153.1, 152.6, 133.0, 131.3, 128.4, 127.9, 127.6,124.7, 60.9, 60.1, 40.1, 31.7, 26.1, 16.1, 12.8, 12.7, 12.2.

(E)-2,3,5-trimethyl-6-(3-methylnon-2-enyl)-1,4-benzoquinone

Zirconocene dichloride (220 mg, 0.755 mmol) was treated withtrimethylaluminum in heptane (3 mL 2.0 M) and the solvent removed invacuo. Dichloroethane (3 mL) was added and the yellow solution cooled to0° C. prior to slow addition of 450 μL 1-octyne (336 mg, 3.05 mmol). Theice bath was removed after 20 minutes and the reaction warmed to rt over2.5 h at which time it was concentrated in vacuo to a yellow slurry andtriturated with hexanes (4 mL) and the solvent removed in vacuo. Hexanes(3 mL) was added and the liquid cannulated away from the white solids.The solids were washed with 2 mL hexanes and the washings combined,concentrated to a yellow oil, dissolved into THF (5 mL) and cooled to−78° C. 2-(chloromethyl)-3,5,6-trimethyl-1,4-benzoquinone (400 mg, 2.01mmol) was dissolved into THF (3 mL) and transferred to the vinyl alanevia cannula with THF (2×1 mL) to assist the transfer.bis-(Triphenylphosphine)nickel dichloride (66.2 mg, 0.101 mmol) wassuspended in THF (2 mL) and treated with n-BuLi in hexanes (1.6 M, 0.20mmol) to give a clear, blood red solution which was added via cannula tothe chilled vinyl alane, chloromethyl quinone solution. The reaction waswarmed to room temperature overnight and chilled to −20 C prior toaddition of a 1 M citric acid solution (20 mL). The solution was stirredfor 0.75 h, EtOAc (10 mL) added and the layers separated. The aqueousphase was extracted EtOAc (2×10 mL), the combined organics washed withbrine (2×10 mL), dried over anhydrous Na₂SO₄ and concentrated to ayellow oil. Multiple flash chromatography yielded 138.7 mg (23.9%) of(E)-2,3,5-trimethyl-6-(3-methylnon-2-enyl)-1,4-benzoquinone as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ4.91 (t, J=6.8 Hz, 1H), 3.18 (d, J=6.8 Hz,2H), 2.00 (s, 9H), 1.92 (t, J=8.0 Hz, 2H), 1.70 (s, 3H), 1.34-1.21 (m,8H), 0.84 (t, J=6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 187.8, 187.0,143.2, 140.2, 137.4, 119.1, 39.6, 31.6, 28.8, 27.7, 25.5, 22.6, 16.1,14.0, 12.3, 12.1

(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile

1-((E)-6-iodo-3-methylhex-2-enyl)-2,5-dimethoxy-3,4,6-trimethylbenzene(412 mg, 1.024 mmol) was combined with NaCN (247.7 mg) and dissolved inDMF (2 mL). The reaction was stirred for 25 h at 45° C. then cooled toroom temperature. To the mixture was added H₂O (10 mL) followed by MTBE(6 mL) and the layers separated. The aqueous phase was extracted intoMTBE (4×6 mL) and the combined organics washed with H₂O (2×5 mL)followed by saturated NaCl solution (2×5 mL) and dried over Na₂SO₄. Theorganics were concentrated to give(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile asa pale yellow oil, 306.4 mg (99.0%). ¹H NMR (400 MHz, CDCl₃) d 5.14 (t,J=6.4 Hz, 1H), 3.65 (s, 6H), 3.37 (d, J=6.8 Hz, 2H), 2.26 (t, J=7.2 Hz,2H), 2.18 (s, 9H), 2.12 (t, J=7.2 Hz, 2H), 1.76 (m, 4H). ¹³C NMR (100MHz, CDCl₃) d 153.1, 152.6, 132.5, 131.0, 128.5, 128.0, 125.4, 119.7,60.8, 60.1, 38.2, 38.2, 26.1, 23.5, 16.4, 15.9, 12.8, 12.7, 12.2.

N-((E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl)acetamide

LAH (102 mg, 2.69 mmol) in THF (5 mL) was treated with(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile(150.9 mg, 0.5006 mmol) in THF (5 mL) by dropping funnel over 10minutes. After 4.25 h, the cloudy gray solution was placed in a roomtemperature water bath and treated carefully with Na₂SO₄.10H₂O (996 mg).The bath was removed and the reaction stirred vigorously for 1 hfollowed by an additional Na₂SO₄.10H₂O (959 mg) and stirring overnight.The white precipitate was separated from the organics, rinsed with EtOAc(5×5 mL) and concentrated to a clear, colorless oil of(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-amine.

The crude amine was dissolved into Et₃N (2 mL) and treated with neatAc₂O (0.75 mL) over 5 minutes. The reaction exothermed slightly and wasallowed to stir overnight at room temperature before being quenched byaddition of H₂O (10 mL) and EtOAc (10 mL). The layers were separated andthe aqueous phase extracted using EtOAc (3×10 mL). The combined organicswere washed with H₂O (2×10 mL) and saturated NaCl solution (2×15 mL)before being dried over anhydrous Na₂SO₄ and concentration to a brownoil. Flash chromatography on silica gaveN-((E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl)acetamideas an off-white crystalline solid, 130 mg (74.7%)

Data for(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-amine:¹H NMR (400 MHz, CDCl₃) d 5.05 (t, J=6.0 Hz, 1H), 3.63 (s, 6H), 3.35 (d,J=6.0 Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), 2.16 (s, 9H), 1.97 (m, 2H), 1.75(s, 3H), 1.63 (m, 2H), 1.38 (m, 3H). ¹³C NMR (100 MHz, CDCl₃) d 152.9,152.6, 134.9, 131.5, 128.1, 127.8, 127.6, 123.2, 62.1, 60.7, 60.0, 42.0,39.3, 33.4, 26.0, 16.1, 12.7, 12.6, 12.0.

Data forN-((E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl)acetamide:¹H NMR (400 MHz, CDCl₃) d 5.66 (br s, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.63(s, 6H), 3.34 (d, J=6.4 Hz, 2H), 3.18 (q, J=5.6 Hz, 2H), 2.17 (s, 9H),1.94 (m, 5H), 1.74 (S, 3H), 1.41 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) d169.9, 153.0, 152.6, 134.6, 131.4, 128.2, 127.8, 127.6, 123.5, 60.8,60.0, 39.5, 39.1, 29.1, 26.1, 25.1, 23.2, 16.1, 12.7, 12.6, 12.1.

N-((5E)-5-methyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)hept-5-enyl)acetamide

Ceric ammonium nitrate (90.1 mg, 0.164 mmol) was dissolved into H₂O (0.5mL) and AcCN (0.5 mL) and cooled to 0° C. A solution containing 25.2 mgN-((E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl)acetamide(0.0725 mmol) in AcCN (1 mL) and CH₂Cl₂ (0.25 mL) was added over 0.5min. The reaction was stirred for 0.75 h at 0° C. then diluted with H₂O(2 mL). The layers were separated and the organic phase diluted withEtOAc (5 mL) and washed with H₂O (3×2 mL). The combined aqueous phasewas back extracted using EtOAc (3×4 mL) and discarded. The combinedorganics were washed with brine (2×3 mL), dried over Na₂SO₄,concentrated in vacuo and subjected to flash chromatography (SiO₂) gaveN-((5E)-5-methyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)hept-5-enyl)acetamideas a bright yellow liquid. ¹H NMR (400 MHz, CDCl₃) d 5.61 (br s, 1H),3.20 (m, 4H), 2.01 (m, 14H), 1.72 (s, 3H), 1.41 (m, 2H). ¹C NMR (100MHz, CDCl₃) d 187.9, 187.1, 170.0, 143.1, 140.43 140.37, 136.7, 119.9,60.1, 39.5, 39.2, 29.1, 25.6, 25.0, 23.3, 16.1, 12.4, 12.2.

(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enal

(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile(178 mg, 0.59 mmol) was dried azeotropically with toluene in vacuo (3×2mL), redissolved into toluene (3 mL) and cooled to 0° C. DIBALH (1.0 Min heptane, 0.9 mmol) was added over 3 minutes dropwise. After 1 h, H₂O(2 ml) and aqueous H₂SO₄ (6 mL 2.5 M) were added and the mixture letwarm to room temperature for 2.5 h. MTBE (5 mL) was added, the layersseparated and the aqueous phase extracted 3×5 mL MTBE. The combinedorganics were washed with brine (10 mL), dried over anhydrous Na₂SO₄ andconcentrated to give(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enal as acolorless oil.

(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol

Crude(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enenitrile inMeOH (3 mL) was cooled to 0° C. and treated with NaBH₄ (64.3 mg, 1.74mmol), which gave immediate effervescence. After 12 h, H₂O (10 mL) wasadded (caution: copious gas evolution), MTBE (10 mL) was added,separated and the aqueous phase extracted with MTBE (3×10 mL). Thecombined organics were washed with H₂O (10 mL), brine (10 mL), driedover Na₂SO₄ and concentrated to give(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol as apale yellow oil.

(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl acetate

(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol inpyridine (2 mL) was treated with Ac₂O (2 mL) at 0° C. and let stirovernight. The reaction was quenched with H₂O (10 mL) followed byaddition of EtOAc (10 mL) and separated. The aqueous phase was extractedwith EtOAc (3×10 mL) and the combined organics washed with brine (15mL), dried over anhydrous Na₂SO₄ and concentrated to a yellow oil. Flashchromatography on silica yielded 77.9 mg (62.3%) of(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl acetateas a clear oil.

(E)-5-methyl-7-(2,4,7-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)hept-5-enylacetate

Ceric ammonium nitrate (270 mg, 0.498 mmol) was dissolved into H₂O (0.75mL) and AcCN (1.5 mL) and the solution chilled to 0° C. 77.9 mg of(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl acetate(0.223 mmol) in AcCN (1.5 mL) was added over 2 minutes and the darkorange solution stirred for 0.5 h. H₂O (3 mL) and EtOAc (3 mL) were thenadded, the layers separated and the organics washed 2×2 mL H₂O. Thecombined aqueous phase was back extracted 3×5 mL EtOAc and the combinedorganics washed 2×5 mL saturated NaCl solution and dried over anhydrousNa₂SO₄. The resulting yellow liquid was concentrated to a yellow oil andsubjected to flash chromatography, which yielded 25.8 mg of(E)-5-methyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)hept-5-enylacetate as a bright yellow oil (36.2%). ¹H NMR (400 MHz, CDCl₃) d 4.95(t, J=6.4 Hz, 1H), 4.02 (t, J=6.8 Hz, 2H), 3.19 (d, J=6.8 Hz, 2H), 2.01(m, 11H), 1.73 (s, 3H), 1.55 (m, 2H) 1.42 (m, 2H). ¹³C NMR (100 MHz,CDCl₃) d 187.9, 187.0, 171.1, 143.0, 140.4, 140.3, 136.7, 119.9, 64.4,39.1, 28.1, 25.6, 24.1, 20.9, 16.1, 12.3, 12.1.

(E)-2-(7-hydroxy-3-methylhept-2-enyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione

(E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-en-1-ol (29.7mg, 0.097 mmol) in AcCN (0.5 mL) with 2 drops of H₂O was cooled to 0° C.CAN (114.7 mg, 0.209 mmol) was dissolved into AcCN (0.2 mL) and H₂O (0.5mL) and added to a stirred solution of alcohol at 0° C. The reaction wasstirred at 0° C. for 1 h and H₂O (2 mL) and EtOAc (2 mL) was added, thelayers separated and the aqueous phase extracted 3×2 mL EtOAc. Thecombined organics were washed 2×2 mL saturated brine, dried overanhydrous Na₂SO₄ and concentrated to a yellow oil. Flash chromatographyyielded(E)-2-(7-hydroxy-3-methylhept-2-enyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione(2.2 mg) as a yellow oil (8.2%). ¹³C NMR (100 MHz, CDCl₃) δ 187.9,187.0, 143.1, 140.4, 104.3, 134.0, 119.7, 77.2, 62.9, 39.3, 32.3, 25.6,24.0, 16.2, 12.4, 12.3, 12.2

The disclosures of all publications, patents, patent applications andpublished patent applications referred to herein by an identifyingcitation are hereby incorporated herein by reference in their entirety.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A compound of the formula:

where n is an integer from 2-8 inclusive, and each unit is the same ordifferent; wherein the bonds indicated with dashed lines are single ordouble; wherein R₁, R₂ and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl, and wherein atleast one of R₁, R₂, and R₃ is independently selected from the groupconsisting of —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl; with the provisothat when R₂ is —C₁-C₅ alkyl and R₁ is —H, then R₃ is not —H; where R₄is selected from the group consisting of —H, —OH, —S—R₅, —F, —Cl, —I,and —NR₅R₆; where X is selected from the group consisting of —H, —NR₇R₈,—OR₉ and —(CH₂)₂C(CH₃)₂OH; where R₅ and R₆ are independently selectedfrom the group consisting of —H, —C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅haloalkyl, aryl, heteroaryl, —(C═O)—C₁-C₈ alkyl, —(C═O)—C₁-C₈alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, and —(C═O)—C₀-C₈ alkyl-C₆-C₁₀ aryl-C₁-C₈alkyl, or where R₅ and R₆ selected from these groups are combined toform a ring; where R₇ and R₈ are independently selected from the groupconsisting of —H, —C₁-C₈ alkyl, —C₁-C₈ haloalkyl, and —(C═O)—C₁-C₈alkyl, or where either one of R₇ and R₈ is independently selected fromthe group consisting of —(C═O)—C₁-C₈ haloalkyl; —(C═O)—NH₂;—(C═O)—NHC₁-C₈ alkyl; —(C═O)—NHC₁-C₈ haloalkyl; —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from thegroup consisting of —NH—, —N(C₁-C₄ alkyl)-, —O—, and —S— is optionallyincorporated in the ring formed by R₂₀ and R₂₁ and the nitrogen atom towhich they are attached; —(C═O)—OC₁-C₈ alkyl; —(C═O)—OC₁-C₈ haloalkyl;—S(O)₂C₁-C₈ alkyl; —S(O)₂aryl; and —S(O)₂aralkyl; and where the other ofR₇ and R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈ haloalkyl or where R₇ and R₈selected from these groups are combined to form a ring, or where R₇ is—(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₇ and R₈together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from thegroup consisting of —NH—, —N(C₁-C₄ alkyl)-, —O—, and —S— is optionallyincorporated in the ring formed by R₇ and R₈ and the nitrogen atom towhich they are attached; where R₉ is independently selected from thegroup consisting of —H; —C₁-C₈ alkyl; —C₁-C₈ haloalkyl; —(C═O)—C₁-C₈alkyl; —(C═O)—C₁-C₈ haloalkyl; —(C═O)—NH₂; —(C═O)—NHC₁-C₈ alkyl;—(C═O)—NHC₁-C₈ haloalkyl; —(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁is —(CH₂)_(q)—, p and q are independently integers between 0 and 7inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁ together withthe nitrogen atom to which they are attached combine to form a 3- to8-membered ring, and where another group selected from the groupconsisting of —NH—, —N(C₁-C₄ alkyl)-, —O—, and —S— is optionallyincorporated in the ring formed by R₂₀ and R₂₁ and the nitrogen atom towhich they are attached; —(C═O)—OC₁-C₈ alkyl; —(C═O)—OC₁-C₈ haloalkyl;—S(O)₂C₁-C₈ alkyl; —S(O)₂aryl; and —S(O)₂; with the provisos that whenn=3 and R₄ is —H or —OH, then X is not —H, and that the compound is not

or any stereoisomer, mixture of stereoisomers, or salt thereof.
 2. Thecompound of claim 1, where R₄ is —H or —OH.
 3. The compound of claim 1,wherein at least two of R₁, R₂, and R₃ are independently selected fromthe group consisting of —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅ alkenyl,—C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl.
 4. Thecompound of claim 3, wherein R₁, R₂, and R₃ are independently selectedfrom the group consisting of —C₂-C₅ alkyl, —C₂-C₅ haloalkyl, —C₂-C₅alkenyl, —C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl. 5.A compound of the formula:

where n is an integer from 1-9 inclusive, and each unit is the same ordifferent; wherein the bonds indicated with dashed lines are single ordouble; wherein R₁, R₂ and R₃ are independently selected from the groupconsisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl, —C₂-C₅haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl, with the provisothat when R₂ is —C₁-C₅ alkyl and R₁ is —H, then R₃ is not —H; where R₄is selected from the group consisting of —H, —O—R₅, —S—R₅, —F, —Cl, —Br,—I, and —NR₅R₆; where X is selected from the group consisting of —NR₇R₈,—OR₉ and —(CH₂)₂C(CH₃)₂OH; where R₅ and R₆ are independently selectedfrom the group consisting of —H, —C₁-C₅ alkyl, —C₃-C₆ cycloalkyl, —C₁-C₅haloalkyl, aryl, heteroaryl, —(C═O)—C₁-C₈ alkyl, and —(C═O)—C₀-C₈alkyl-C₆-C₁₀ aryl-C₀-C₈ alkyl, or where R₅ and R₆ selected from thesegroups are combined to form a ring; where R₇ and R₈ are independentlyselected from the group consisting of —H, —C₁-C₈ alkyl, —C₁-C₈haloalkyl, and —(C═O)—C₁-C₈ alkyl, or where either one of R₇ and R₈ isindependently selected from the group consisting of —(C═O)—C₁-C₈haloalkyl; —(C═O)—NH₂; —(C═O)—NHC₁-C₈ alkyl; —(C═O)—NHC₁-C₈ haloalkyl;—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from the group consisting of —NH—, —N(C₁-C₄ alkyl)-, —O—,and —S— is optionally incorporated in the ring formed by R₂₀ and R₂₁ andthe nitrogen atom to which they are attached; —(C═O)—OC₁-C₈ alkyl;—(C═O)—OC₁-C₈ haloalkyl; —S(O)₂C₁-C₈ alkyl; —S(O)₂aryl; and—S(O)₂aralkyl; and where the other of R₇ and R₈ is —H, —C₁-C₈ alkyl or—C₁-C₈ haloalkyl or where R₇ and R₈ selected from these groups arecombined to form a ring, or where R₇ is —(CH₂)_(p)—, R₈ is —(CH₂)_(q)—,p and q are independently integers between 0 and 7 inclusive, p+q isbetween 2 and 7 inclusive, R₇ and R₈ together with the nitrogen atom towhich they are attached combine to form a 3- to 8-membered ring, andwhere another group selected from the group consisting of —NH—, —N(C₁-C₄alkyl)-, —O—, and —S— is optionally incorporated in the ring formed byR₇ and R₈ and the nitrogen atom to which they are attached; where R₉ isindependently selected from the group consisting of —H; —C₁-C₈ alkyl;—C₁-C₈ haloalkyl; —(C═O)—C₁-C₈ alkyl; —(C═O)—C₁-C₈ haloalkyl;—(C═O)—NH₂, —(C═O)—NHC₁-C₈ alkyl; —(C═O)—NHC₁-C₈ haloalkyl;—(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q areindependently integers between 0 and 7 inclusive, p+q is between 2 and 7inclusive, R₂₀ and R₂₁ together with the nitrogen atom to which they areattached combine to form a 3- to 8-membered ring, and where anothergroup selected from the group consisting of —NH—, —N(C₁-C₄ alkyl)-, —O—,and —S— is optionally incorporated in the ring formed by R₂₀ and R₂₁ andthe nitrogen atom to which they are attached; —(C═O)—OC₁-C₈ alkyl;—(C═O)—OC₁-C₈ haloalkyl; —S(O)₂C₁-C₈ alkyl; —S(O)₂aryl; and —S(O)₂; withthe provisos that when R₁ and R₂ are -OMe and R₃ is -Me, then either R₄is neither —H nor —OH, or X is neither —OH nor —(CH₂)₂C(CH₃)₂OH, andthat the compound is not

or any stereoisomer, mixture of stereoisomers, or salt thereof.
 6. Thecompound of claim 5, wherein X is —OH or —NH₂.
 7. The compound of claim6 wherein the compound is of the formula:

or any stereoisomer, mixture of stereoisomers, or salt thereof.
 8. Thecompound of claim 5 wherein X is —(CH₂)₂C(CH₃)₂OH.
 9. The compound ofclaim 8 of the formula:

or any stereoisomer, mixture of stereoisomers, or salt thereof.
 10. Acompound of the formula:

where n is an integer from 0 to 9 inclusive, and each unit is the sameor different; wherein the bonds indicated with dashed lines are singleor double; wherein R₁, R₂ and R₃ are independently selected from thegroup consisting of —H, —C₁-C₅ alkyl, —C₁-C₅ haloalkyl, —C₂-C₅ alkenyl,—C₂-C₅ haloalkenyl, —C₂-C₅ alkynyl, and —C₂-C₅ haloalkynyl, with theproviso that when R₂ is —C₁-C₅ alkyl and R₁ is —H, then R₃ is not —H;where R₄ is selected from the group consisting of F, Cl, and I; where Xis selected from the group consisting of —H, —NR₇R₈, —OR₉, and—(CH₂)₂C(CH₃)₂OH; where R₇ and R₈ are independently selected from thegroup consisting of —H, —C₁-C₈ alkyl, —C₁-C₈ haloalkyl, and —(C═O)—C₁-C₈alkyl, or where either one of R₇ and R₈ is independently selected fromthe group consisting of —(C═O)—C₁-C₈ haloalkyl; —(C═O)—NH₂;—(C═O)—NHC₁-C₈ alkyl; —(C═O)—NHC₁-C₈ haloalkyl; —(C═O)—NR₂₀R₂₁ where R₂₀is —(CH₂)_(p)—, R₂₁ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from thegroup consisting of —NH—, —N(C₁-C₄ alkyl)-, —O—, and —S— is optionallyincorporated in the ring formed by R₂₀ and R₂₁ and the nitrogen atom towhich they are attached; —(C═O)—OC₁-C₈ alkyl; —(C═O)—OC₁-C₈ haloalkyl;—S(O)₂C₁-C₈ alkyl; —S(O)₂aryl; and —S(O)₂aralkyl; and where the other ofR₇ and R₈ is —H, —C₁-C₈ alkyl or —C₁-C₈ haloalkyl or where R₇ and R₈selected from these groups are combined to form a ring, or where R₇ is—(CH₂)_(p)—, R₈ is —(CH₂)_(q)—, p and q are independently integersbetween 0 and 7 inclusive, p+q is between 2 and 7 inclusive, R₇ and R₈together with the nitrogen atom to which they are attached combine toform a 3- to 8-membered ring, and where another group selected from thegroup consisting of —NH—, —N(C₁-C₄ alkyl)-, —O—, and —S— is optionallyincorporated in the ring formed by R₇ and R₈ and the nitrogen atom towhich they are attached; where R₉ is independently selected from thegroup consisting of —H; —C₁-C₈ alkyl; —C₁-C₈ haloalkyl; —(C═O)—C₁-C₈alkyl; —(C═O)—C₁-C₈ haloalkyl; —(C═O)—NH₂; —(C═O)—NHC₁-C₈ alkyl;—(C═O)—NHC₁-C₈ haloalkyl; —(C═O)—NR₂₀R₂₁ where R₂₀ is —(CH₂)_(p)—, R₂₁is —(CH₂)_(q)—, p and q are independently integers between 0 and 7inclusive, p+q is between 2 and 7 inclusive, R₂₀ and R₂₁ together withthe nitrogen atom to which they are attached combine to form a 3- to8-membered ring, and where another group selected from the groupconsisting of —NH—, —N(C₁-C₄ alkyl)-, —O—, and —S— is optionallyincorporated in the ring formed by R₂₀ and R₂₁ and the nitrogen atom towhich they are attached; —(C═O)—OC₁-C₈ alkyl; —(C═O)—OC₁-C₈ haloalkyl;—S(O)₂C₁-C₈ alkyl; —S(O)₂aryl; and —S(O)₂; or any stereoisomer, mixtureof stereoisomers, or salt thereof.
 11. The compound of claim 10 of theformula:

or any stereoisomer, mixture of stereoisomers, or salt thereof.
 12. Thecompound of claim 1, additionally comprising a pharmaceuticallyacceptable excipient.
 13. The compound of claim 5, additionallycomprising a pharmaceutically acceptable excipient.
 14. The compound ofclaim 10, additionally comprising a pharmaceutically acceptableexcipient.